ClinVar Miner

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

dbSNP: rs28937893
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 tute.org/; 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 2023-07-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11709537, 11709538, 17492394, 12490066, 12707188, 28432734, 29529044, 29277467, 36208030, 36225977, 34599366, 36098976)
Invitae RCV000522349 SCV002239441 pathogenic not provided 2023-02-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 4520). This missense change has been observed in individual(s) with autosomal dominant nonsyndromic deafness (PMID: 11709537, 11709538; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28937893, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 716 of the WFS1 protein (p.Ala716Thr).
OMIM RCV000004778 SCV000024954 pathogenic Autosomal dominant nonsyndromic hearing loss 6 2007-01-01 no assertion criteria provided literature only

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