ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2146G>A (p.Ala716Thr) (rs28937893)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000599627 SCV000202064 pathogenic Rare genetic deafness 2016-08-16 criteria provided, single submitter clinical testing The p.Ala716Thr variant in WFS1 has been reported in six families with low frequ ency sensorineural hearing loss and was shown to segregate in >30 affected famil y members (Bespalova 2001, Young 2001, Fukuoka 2007, LMM Data). All individuals heterozygous for the p.Ala716Thr variant were reported to have only hearing loss , and one individual homozygous for the variant had clinical features of Wolfram syndrome (Young 2001). This variant has been identified in 1/30736 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti; dbSNP rs28937893). In summary, this variant meets criteria to be clas sified as pathogenic for autosomal dominant hearing loss; however, its clinical significance for autosomal recessive Wolfram syndrome is uncertain. ACMG/AMP Cri teria applied: PP1_Strong; PM2; PS4_Moderate; PP3.
GeneDx RCV000522349 SCV000616989 likely pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing The A716T variant in the WFS1 gene has been reported in the heterozygous state in association with low frequency non-syndromic hearing loss and in the homozygous state in an individual with features suggestive of Wolfram syndrome (Besplova et al., 2001; Young et al., 2001; Fukuoka et al., 2007). The A716T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A716T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A716T as a likely pathogenic variant.
OMIM RCV000004778 SCV000024954 pathogenic Autosomal dominant nonsyndromic deafness 6 2007-01-01 no assertion criteria provided literature only

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