hu1187FF - GET-Evidence variant report

Variant report for hu1187FF

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VariantClinical
Importance
ImpactAllele
freq
Summary
1SERPINA1-E366KHighWell-establishedWell-established pathogenic

Recessive, Carrier (Heterozygous)
0.0117122This is also called the "Pi Z" or "Z" allele. When homozygous (acting in a recessive manner) this variant is the major cause of severe alpha-1-antitrypsin deficiency (95% of cases) which often leads to emphysema or chronic obstructive pulmonary disease (COPD) and liver disease in adults and children. Heterozygosity for this variant may also be associated with increased rate of lung or liver problems, especially when combined with another variant with reduced function (compound heterozygous).1
2LRP5-V667MHighUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.0413646This variant has been implicated in causing osteoporosis-pseudoglioma syndrome in a recessive manner. The gene is strongly implicated in causing the disease, but an insufficient number of controls means this variant's observation lacks statistical significance. The condition manifests in childhood with early onset osteoporosis and eye problems.1
3PPARG-P12AModerateUncertainUncertain not reviewed

Unknown, Heterozygous
0.08867821
4MEFV-E148QModerateUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.0120929Some reports believe this cause Familial Mediterranean Fever in a recessive manner with reduced penetrance (i.e. not all get the disease). However, these reports lack strong statistical significance; other studies argue the variant is not associated with the disease.1
5SERPINA1-E288VLowWell-establishedWell-established pathogenic

Recessive, Carrier (Heterozygous)
0.0304889This variant represents the PiS variant in alpha-1-antitrypsin deficiency where a homozygous individual has 60% enzymatic activity. This variant alone is unlikely to much effect, but 3-4% of heterozygotes are compound heterozygous with the more severe PiZ variant, which is associated with an increased risk of emphysema and COPD.1
6COL4A1-Q1334HLowLikelyLikely pathogenic

Dominant, Homozygous
0.324689This common variant has been associated with arterial stiffness and, in Japanese, a small increased risk of myocardial infarction (MI, a.k.a. heart attack). This last observation supported a dominant effect for this variant and, assuming a lifetime risk of 15% for MI, we estimate carriers have an additional risk of 0.5-3%.1
7NOD2-R702WLowLikelyLikely pathogenic

Complex/Other, Heterozygous
0.0334821NOD2 encodes a protein involved in bacterial recognition. This variant is associated with Crohn's disease in European populations, but not in Korean or Japanese groups.1
8MTRR-I49MLowLikelyLikely pathogenic

Recessive, Carrier (Heterozygous)
0.451199This common variant (HapMap allele frequency of 31.3%) in a protein involved in folate (B9) and cobalamin (B12) metabolism and is often reported as "MTRR I22M" (an alternative transcript position). Mothers homozygous for this variant are associated with having around a increased chance of a child with Down syndrome (risk of 0.4%, average risk in population is 0.25%). Notably, age plays a far larger role in the rate of Down syndrome (risk is 4.5% for a mother 45-years-of-age), and it is unknown how this variant may combine with the effect of age. There are conflicting reports associating this variant with incidence of neural tube defects, possibly when combined with MTHFR A222V.1
9ELAC2-S217LLowUncertainUncertain pathogenic

Complex/Other, Heterozygous
0.273471Reported to be associated with increased susceptibility to prostate cancer, but later studies weaken the hypothesis. Xu et al.'s meta-analysis concludes that there is a small but significant increased risk (OR = 1.13). Assuming a lifetime risk of 16% for prostate cancer we calculate this leads to an increased risk of ~1.5% (17.5% total).1
10RNASEL-R462QLowUncertainUncertain pathogenic

Complex/Other, Heterozygous
0.278026Associated with increased risk of prostate cancer in individuals who already have a family history of prostate cancer, but studies have been unable to replicate this finding in sporadic (non-familial) prostate cancer cases.1
11LRP5-A1330VLowUncertainUncertain pathogenic

Complex/Other, Heterozygous
0.110367In a study of a UK population this variant was associated with a small increased risk of osteoporosis and osteoporotic bone fractures, with each copy of the variant presumed to have an additive effect. A study in Chinese young men failed to find an association with peak bone density. 1
12ERCC6-R1213GLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.196877When homozygous, this variant may cause Cockayne Syndrome, which is a severe autosomal-recessive disorder characterized by abnormal early growth and development, abnormal sensitivity to sunlight, and premature aging. Cockayne Syndrome Type I and Type II lead to death in early childhood. Several other variants in the ERCC6 gene are linked to Cockayne Syndrome. This variant may also be linked to age-related macular degeneration like other ERCC6 variants, and has been linked to colorectal cancer in one study. 1
13SP110-L425SLowUncertainUncertain pathogenic

Unknown, Homozygous
0.863357This variant is associated with a slightly increased risk of tuberculosis. It is unclear whether it is itself causal, or in linkage disequilibrium with some other causal variant that has a stronger effect.1
14TP53-P72RLowUncertainUncertain pathogenic

Unknown, Heterozygous
0.627743This is a common variant was first reported as a polymorphism. It has since had mixed associations with cancer: Storey et al. conclude a 7x *increased* risk of HPV cancer for homozygotes vs hets, but Jones et al. find a 1.98x *decreased* risk for colorectal cancer. This variant may have significant impact on particular cancers, but it is unclear what effect it has on the overall burden of cancer.1
15BRCA2-N372HLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.23656This is a common variant of BRCA2 (HapMap allele frequency of 23%). The variant is weakly associated with an increased chance of breast cancer, and zygosity of the variant is associated with sex of children: male children are more likely to be homozygous for this variant, female children are more likely to be heterozygous.1
16H6PD-R453QLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.308886This common variant may have a small pathogenic effect by contributing to cortisone reductase deficiency (a rare abnormality) when homozygous and combined with a serious pathogenic variant. The same authors have tested and ruled out a contribution to polycystic ovary syndrome (similar phenotype, more common disease).1
17ITPA-P32TLowWell-establishedWell-established pharmacogenetic

Recessive, Carrier (Heterozygous)
0.0609779This variant is associated with inosine triphosphate pyrophosphohydrolase deficiency and may be associated with an adverse reaction to thiopurine drugs (which are used as immunosuppressants). Homozygotes have no detectable ITPase activity, individuals compound heterozygous with another less severe mutation also have severely reduced enzyme activity.1
18rs1544410LowUncertainUncertain pharmacogenetic

Unknown, Heterozygous
0.351562rs1544410 is a Vitamin D Receptor (VDR) single nucleotide polymorphism. It is unlikely that it has functional significance because it is located in an intron (Liu et. al.), but it is in strong linkage disequilibrium with rs731236 (Dvornyk et al), which is located in an exon. 1
19FUT2-W154XModerateWell-establishedWell-established protective

Recessive, Carrier (Heterozygous)
0.490519This recessive protective variant confers resistance to norovirus (which causes stomach flu). 20% of Caucasians and Africans are homozygous for this variant and are "non-secretors": they do not express ABO blood type antigens in their saliva or mucosal surfaces. Most strains of norovirus bind to these antigens in the gut, and so this non-secretor status confers almost total resistantance to most types of norovirus. There are notable exceptions, some strains of norovirus bind a different target and are equally infectious for secretors and non-secretors.1
20PRNP-M129VLowWell-establishedWell-established protective

Complex/Other, Homozygous
0.339561This variant is associated with some protective effects for prion disease -- individuals homozygous for this variant are less susceptible to Creutzfeldt-Jakob, and Papua New Guinea individuals heterozygotes at this site are less susceptible to kuru. 1
21CFH-V62ILowLikelyLikely protective

Complex/Other, Heterozygous
0.391616Associated with a decreased risk for age related macular degeneration (ARMD). Homozygotes for this have a 4-5% decreased attributable risk (3-4% vs. average 8% risk), heterozygotes have slightly lower than average risk (7%). Non-carriers have an increased risk (12-13%). ARMD impairs sharp vision as age progresses. While there is no cure, treatment can slow progression of the disease and environmental factors (smoking and obesity) contribute to higher risk.1
22KCNJ11-K23ELowLikelyLikely protective

Unknown, Heterozygous
0.738148This variant is associated with decreased risk of type 2 diabetes. It is unclear whether this variant has additive effects, or acts in a dominant or recessive manner. Assuming diabetes has a lifetime risk of 36%, we estimate a decreased risk of around 1-2% per copy of this variant.1
23TOR1A-D216HLowLikelyLikely protective

Unknown, Heterozygous
0.102993This SNP has been shown to be benign and play a protective role against Dystonia. 1
24LIG4-A3VLowUncertainUncertain protective

Dominant, Heterozygous
0.035843One report has associated this with a decreased risk of multiple myeloma.1
25MTR-D919GLowUncertainUncertain protective

Complex/Other, Heterozygous
0.217234This variant was weakly associated with a protective effect vs. colorectal cancer, but only in individuals with low alcohol consumption. 1
26DTNBP1-P272SLowUncertainUncertain protective

Recessive, Carrier (Heterozygous)
0.0351366Possibly a slight protective effect against colorectal cancer if homozygous.1
27PKD1-A4059VLowLikelyLikely benign

Unknown, Heterozygous
0.0570413Probably benign.1
28CACNA1S-L458HLowLikelyLikely benign

Unknown, Heterozygous
0.27282Common polymorphism1
29LOXL1-R141LLowUncertainUncertain benign

Complex/Other, Heterozygous
0.255899Associated with exfoliative glaucoma & syndrome (XFG & XFS) in various populations, but with contradicting results (protective in Caucasians, pathogenic in Japanese). Based on this it seems the variation itself -- although it affects protein structure -- is not itself causing disease. Instead it is likely associated with other nearby causal variants. As such, it is evaluated as benign by GET-Evidence (which focuses on reporting causal variants). See detailed variant report for disease risk associations.1
30TPCN2-G734ELowUncertainUncertain benign

Unknown, Homozygous
0.286166Pigmentation allele.1
31GUCY2D-A52SLowUncertainUncertain benign

Recessive, Carrier (Heterozygous)
0.21016One publication suggested that this variant possibly causes Leber's congenital amaurosis in a recessive manner, but the frequency data (36% in 1000 genomes) contradicts any significant pathogenic effect.1
32TXNDC3-I338TLowUncertainUncertain benign

Unknown, Heterozygous
0.0377604Tentatively classified as benign, but predicted to be damaging and other variants in this gene are implicated in causing primary ciliary dyskinesia (situs inversus, chronic sinusitis, and bronchiectasis).1
33GAA-D91NLowUncertainUncertain benign

Recessive, Carrier (Heterozygous)
0.0237033This is a rare but non-pathogenic coding polymorphism in GAA that creates variant allozyme, known as GAA*2. 1
34FMO3-V257MLowUncertainUncertain benign

Unknown, Heterozygous
0.0570738This common variant (HapMap allele frequency of 9.2%) appears to have no functional effect. OMIM has recorded it as having been seen homozygously in an individual with Trimethylaminuria, but Treacy et al. 1998 conclude it is a polymorphism.1
35FANCA-S1088FLowUncertainUncertain benign

Unknown, Heterozygous
0.0584681Probably benign. One report hypothesized this variant causing Fanconi Anemia, but the allele frequency (3-7%) is high enough to contradict a highly penetrant pathogenic effect. Later authors have concluded this is a polymorphism, not pathogenic.1
36TYR-S192YLowUncertainUncertain benign

Unknown, Heterozygous
0.270682This variant is reported to affect skin pigmentation. It is associated with lighter skin in South Asians (OR 4-5) and with a lack of freckles in Europeans (OR 1.3).1
37TAS2R38-I296VLowUncertainUncertain benign

Unknown, Homozygous
0.463376This variant is associated with "taster" status of PTC, along with 49P and 262A. Due to linkage disequilibrium, the independent effects of positions 296 and 262 is unclear. The presence of 49P confers taster status in a dominant fashion, but in the absence of 49P, the presence of 262A/296V is still positively associated with tasting PTC.1
38PCSK9-G670ELowUncertainUncertain benign

Unknown, Homozygous
0.888269This variant is likely benign. 1
39RP1-N985YLowUncertainUncertain benign

Unknown, Heterozygous
0.348671Probably benign. One report linked this variant to high triglycerides, but a later paper found a nearby SNP with similar association and suggests that both findings are caused by linkage to an undiscovered causal variant.1
40SLC45A2-L374FLowUncertainUncertain benign

Unknown, Homozygous
0.691764Pigmentation allele for non-black hair, and consequently, possible increased susceptibility to malignant melanoma.1
41APOB-Y1422CLowUncertainUncertain benign

Unknown, Homozygous
0.999628This position is almost certainly an error in the HG18 reference sequence. 1
42PKP2-L366PLowUncertainUncertain benign

Unknown, Heterozygous
0.221231This variant is a benign polymorphism. 1
43SPTA1-A970DLowUncertainUncertain benign

Unknown, Heterozygous
0.0373134This variant, also called alpha-IIa, has been seen frequently in individuals with recessive Hereditary spherocytosis. This appears to be the result of linkage to alpha-LEPRA (a C>T substitution at position -99 of intron 30); A970D is later reported as functionally neutral.1
44TAS2R38-A49PLowUncertainUncertain benign

Unknown, Heterozygous
0.431121This variant is strongly associated with causing the "taster" phenotype of phenylthiocarbamine (PTC) in a dominant manner.1
VariantPrioritization scoreAllele
freq
Num of
articles
Zygosity and Prioritization Score Reasons

Gene search

"GENE" or "GENE A123C":

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