hu72076D (genome_KLM_Full_20140529182248) - GET-Evidence variant report

Variant report for hu72076D (genome_KLM_Full_20140529182248)

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VariantClinical
Importance
ImpactAllele
freq
Summary
1CFTR-G542XHighWell-establishedWell-established pathogenic

Recessive, Carrier (Heterozygous)
0.00167317This is the second most common variant that causes Cystic Fibrosis. It causes Cystic Fibrosis if homozygous or combined with another severely disruptive variant in this gene (e.g. F508Del). Severe variants in this gene can also cause bilateral absence of the vans deferens (causing male infertility) when combined with a less disruptive variant.1
2RYR2-G1886SHighUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.0613424Reported to cause arrhythmogenic right ventricular cardiomyopathy when compound heterozygous with G1885E, although this finding is weakened after correcting for multiple hypotheses and it is unclear what penetrance such a genotype might have, if it is causal.1
3PRPH-D141YHighUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.00365206Hypothesized to cause ALS (or increased susceptibility) in a recessive manner, but this is based on a single observation and may lack statistical significance. The mutant protein appears to form abnormal aggregates.1
4C3-R102GModerateLikelyLikely pathogenic

Complex/Other, Heterozygous
0.152073This variant (also called C3F) is common in Europeans (10.2% allele frequency), and is associated with age-related macular degeneration. In the US, 1.5% of adults over 40 have the disease, but the incidence increases strongly with age (>15% in women over 80). Assuming an average lifetime risk of ~10%, heterozygous individuals have a ~13% risk and homozygous have ~20%.1
5PPARG-P12AModerateUncertainUncertain not reviewed

Unknown, Heterozygous
0.08867821
6AMPD1-Q12XLowLikelyLikely pathogenic

Recessive, Carrier (Heterozygous)
0.0930643Causes Adenosine Deaminase Deficiency in a recessive manner. Most of the time individuals do not report symptoms, but when symptoms do exist they to be post-exercise symptoms of muscle weakness, muscle pain, and getting tired more quickly.1
7MTRR-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
8KRT5-G138ELowLikelyLikely pathogenic

Unknown, Heterozygous
0.0521472This variant is associated with 1.25x increased risk of basal cell carcinoma (common skin cancer, rarely malignant).1
9NOD2-G908RLowLikelyLikely pathogenic

Unknown, Heterozygous
0.0106897This variant is associated with an increased susceptibility to Crohn's disease and other inflammatory bowel diseases (IBD). Assuming an overall prevalence of 0.5% for IBD, this variant implies an increased attributable risk of 2% (5x increased risk, for an overall risk of 2.5% of IBD for people with this variant).1
10MBL2-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
11APOA5-S19WLowLikelyLikely pathogenic

Unknown, Heterozygous
0.0646151This variant, also known as APOA5*3, is associated with higher plasma triglyceride concentrations but no significant correlation with coronary artery disease itself has been found.1
12ELAC2-S217LLowUncertainUncertain pathogenic

Complex/Other, Homozygous
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
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
14H6PD-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
15TP53-P72RLowUncertainUncertain pathogenic

Unknown, Homozygous
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
16ELAC2-A541TLowUncertainUncertain pathogenic

Unknown, Heterozygous
0.0276074This variant is implicated as causing increased susceptibility to prostate cancer. However the variant has always been seen paired with S217L, it is unclear which variant is causal. Evidence is weak for both; one meta-analysis (Severi et al.) concluded that neither variant was pathogenic, a more recent meta-analysis (Xu et al.) found the data to be significant but the odds ratio was not strong and concluded they are "low-penetrance susceptibility markers of prostate cancer".1
17WFS1-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
18ITPA-P32TLowWell-establishedWell-established pharmacogenetic

Recessive, Homozygous
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
19ABCC6-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
20KCNJ11-K23ELowLikelyLikely protective

Unknown, Homozygous
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
21MTR-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
22TYR-R402QLowWell-establishedWell-established benign

Complex/Other, Heterozygous
0.204964This is a frequent pigmentation polymorphism in Europeans that affects function of the Tyrosinase gene. It is associated with blue instead of green eyes and sun sensitivity. For the most part this variant is benign, but many individuals with ocular albinism (which affects only the eyes) carry this variant along with another more severe variant in the same gene.1
23EFHC1-R182HLowLikelyLikely benign

Unknown, Heterozygous
0.0439673Probably benign. OMIM appears to incorrectly interpret literature as linking this variant to juvenile myoclonic epilepsy; the authors report it as a polymorphism.1
24MLH1-I219VLowUncertainUncertain benign

Dominant, Homozygous
0.239822Computational evidence, functional assays, and case/control studies suggest this variant is probably benign.1
25LOXL1-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
26DSPP-R68WLowUncertainUncertain benign

Unknown, Heterozygous
0.143045Probably benign. One report linked this to causing dentinogenesis Imperfecta type II in a large Swedish family, but subsequent publications have observed this is a common variant and conclude it is a nonpathogenic polymorphism.1
27PCSK9-G670ELowUncertainUncertain benign

Unknown, Homozygous
0.888269This variant is likely benign. 1
28APOB-Y1422CLowUncertainUncertain benign

Unknown, Homozygous
0.999628This position is almost certainly an error in the HG18 reference sequence. 1
29AMPD1-P48LLowUncertainUncertain benign

Unknown, Heterozygous
0.0940695Probably benign, ancestral to15173240 pathogenic Q12X mutation.1
30GUCY2D-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
31RP1-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
32MAPT-R370WLowUncertainUncertain benign

Unknown, Heterozygous
0.155549Probably benign.1
33PKP2-L366PLowUncertainUncertain benign

Unknown, Heterozygous
0.221231This variant is a benign polymorphism. 1
34TPCN2-G734ELowUncertainUncertain benign

Unknown, Heterozygous
0.286166Pigmentation allele.1
35SLC45A2-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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