hu5B8771 - GET-Evidence variant report

Variant report for hu5B8771

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VariantClinical
Importance
ImpactAllele
freq
Summary
1MEFV-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
2COL4A1-Q1334HLowLikelyLikely pathogenic

Dominant, Heterozygous
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
3MTRR-I49MLowLikelyLikely pathogenic

Recessive, Homozygous
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
4rs5186LowLikelyLikely pathogenic

Unknown, Heterozygous
0.214878This common noncoding genetic variant has an allele frequency of ~30% and is associated with an increased risk of hypertension. If ~25% of non-carriers have hypertension, Bonnardeaux et al's data predict ~4% increased risk of hypertension per copy of this variant. This SNP is in the 3' noncoding region of the AGTR1 transcript (angiotensin II type 1 receptor), also known as AT2R1 or AT1R, which is a target of hypertension drugs.1
5CETP-A390PLowLikelyLikely pathogenic

Unknown, Heterozygous
0.0388548This variant is associated with slightly lower HDL (good) cholesterol, although it has a negligible effect (around 2 mg/dl).1
6MBL2-G54DLowLikelyLikely pathogenic

Recessive, Carrier (Heterozygous)
0.103923This variant is associated with mannose binding protein deficiency which leads to impaired complement system immune response to mannose-rich pathogens. Patients homozygous for this allele or compound heterozygous are likely to have increased susceptibility to infection, but Hellemann et al. report heterosis for intensive care outcomes in heterozygous subjects. The wild-type version of this gene is known as variant allele A, while this is called variant allele B. See R52C (variant D) and G57E (variant C).1
7TGFB1-R25PLowUncertainUncertain pathogenic

Complex/Other, Heterozygous
0.0488858This variant in a growth factor gene is associated with variation in TGFB1 levels; this has been associated with various pathogenic and some protective effects, including: more hepatic fibrosis progression in hep C patients, lower risk of cleft palate, anticorrelation with longevity, higher risk of myocardial infarction and lower risk of hypertension.1
8HFE-H63DLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.109965There have been some hypotheses that this variant contributes to causing hereditary hemochromatosis, possibly as a compound heterozygote, but some others treat it as a polymorphism. Cys282Tyr is the classic causal variant and itself has very low penetrance. Mouse studies indicates this variant has a similar but weaker effect; if it has any effect at all its penetrance may be quite low and/or require modifier alleles.1
9BRCA2-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
10H6PD-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
11SP110-L425SLowUncertainUncertain pathogenic

Unknown, Heterozygous
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
12CLEC7A-Y238XLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.0632088This variant has been found to impair homan mucosal antifungal defense and was implicated in vulvovaginal candidiasis and mucocutaneous infections in a Dutch family.1
13ERCC6-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
14WFS1-R611HLowUncertainUncertain not reviewed

Recessive, Carrier (Heterozygous)
0.400446This nonsynonymous SNP is associated with Wolfram Syndrome (known as DIDMOAD), which is characterized by early-onset non-autoimmune diabetes mellitus, diabetes insipidus, optic atrophy, and deafness) and to adult Type Two Diabetes Mellitus. The WFS1 gene maps to chromosome 4p16.3. The variant has been shown to be statistically associated with type II diabetes in six UK studies and one study of Ashkenazi Jews (Sandhu, M., et al., Minton et al.).1
15ABCC6-R1268QLowUncertainUncertain pharmacogenetic

Unknown, Heterozygous
0.218907This common polymorphism appears to not have a significant phenotypic impact. A few studies report weak but significant associations with plasma lipids (in Inuits) and thalidomide toxicity.1
16rs1544410LowUncertainUncertain pharmacogenetic

Unknown, Homozygous
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
17FUT2-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
18NPC1-H215RLowLikelyLikely protective

Complex/Other, Heterozygous
0.295687This variant is associated with a reduced risk of obesity, with an additive effect of -0.084 BMI per allele (an average of 0.54 pounds less, per allele, in a 5'6" individual). 1
19KCNJ11-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
20IRS2-G1057DLowUncertainUncertain protective

Unknown, Heterozygous
0.232615a.k.a Gly1057Asp, insulin receptor substrate-2 IRS2. The rs1805097(G) allele is associated with the Gly, and the (A) allele with Asp. A longevity study concluded that rs1805097(A;A) individuals were about twice as likely to live over 85 y/o (odds ratio 2.03, CI:1.39-2.99, p = .0003). 1
21FANCA-M717ILowLikelyLikely benign

Unknown, Heterozygous
0.0216583Rare polymorphism, not considered pathogenic.1
22CACNA1S-L458HLowLikelyLikely benign

Unknown, Homozygous
0.27282Common polymorphism1
23OCA2-R419QLowLikelyLikely benign

Unknown, Heterozygous
0.0565161This variant is associated with eye color, as is OCA2 R305W. Individuals with this variant are reported to be more likely to have green/hazel eyes as opposed to blue/gray eyes. Other variants in this gene are associated with oculocutaneous albinism (albinism which involves skin and eyes).1
24FLT4-N149DLowLikelyLikely benign

Unknown, Heterozygous
0.0725056Other severe variants in this gene are implicated in causing Milroy Disease (primary lymphedema) in a recessive manner. Although this variant is rare (2.3% allele frequency), it is still common enough that it is highly unlikely to have a severe, high penetrance pathogenic effect.1
25MLH1-I219VLowUncertainUncertain benign

Dominant, Heterozygous
0.239822Computational evidence, functional assays, and case/control studies suggest this variant is probably benign.1
26RPGRIP1-A547SLowUncertainUncertain benign

Complex/Other, Homozygous
0.232202Probably benign. Implicated in causing autosomal recessive cone-rod dystrophy, but a later report found the same incidence in controls and concludes it is not causal.1
27LOXL1-R141LLowUncertainUncertain benign

Complex/Other, Homozygous
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
28NOTCH3-P496LLowUncertainUncertain benign

Unknown, Heterozygous
0.015625Presumed benign, seen in two healthy PGP participants.1
29DYNC2H1-Q304LLowUncertainUncertain benign

Unknown, Heterozygous
0.0484135Presumed benign.1
30TYR-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
31APOB-Y1422CLowUncertainUncertain benign

Unknown, Homozygous
0.999628This position is almost certainly an error in the HG18 reference sequence. 1
32GUCY2D-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
33FMO3-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
34ELN-G581RLowUncertainUncertain benign

Unknown, Heterozygous
0.072876Probably a benign SNP, not rare (4.8% allele frequency in GET-Evidence data).1
35CASP8-M1TLowUncertainUncertain benign

Unknown, Heterozygous
0.0310451Probably benign. Although start codons can be extremely disruptive and this gene is implicated in a rare disease (autoimmune lymphoproliferative syndrome), the allele frequency for this variant (2-3%) is high enough to contradict such a strong pathogenic effect. This may be because the gene has many other transcripts that do not include this position as exonic.1
36CD19-R514HLowUncertainUncertain benign

Unknown, Heterozygous
0.0482432Presumed benign.1
37PCSK9-G670ELowUncertainUncertain benign

Unknown, Heterozygous
0.888269This variant is likely benign. 1
38RP1-N985YLowUncertainUncertain benign

Unknown, Homozygous
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
39RAPSN-R58CLowUncertainUncertain benign

Unknown, Heterozygous
0.0778026Reported as non-pathogenic polymorphism. 1
40PKP2-L366PLowUncertainUncertain benign

Unknown, Heterozygous
0.221231This variant is a benign polymorphism. 1
41SLC45A2-L374FLowUncertainUncertain benign

Unknown, Homozygous
0.691764Pigmentation allele for non-black hair, and consequently, possible increased susceptibility to malignant melanoma.1
VariantPrioritization scoreAllele
freq
Num of
articles
Zygosity and Prioritization Score Reasons

Gene search

"GENE" or "GENE A123C":

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