ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.652G>A (p.Asp218Asn) (rs201539845)

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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 RCV000215956 SCV000271251 likely pathogenic Rare genetic deafness 2017-08-17 criteria provided, single submitter clinical testing The p.Asp218Asn variant in MYO7A has been reported in 3 probands with a dominant family history of hearing loss, and segregated with disease in >10 affected rel atives from 2 families (Sun 2011, Iwasa 2016, LMM data). This variant has also b een identified in 8/34418 Latino chromosomes and in 5/126678 European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201539845); however, pathogenic variants may be present at a low frequen cy in the general population. Although loss of function variants in MYO7A primar ily cause autosomal recessive Usher syndrome, several missense variants have bee n reported to segregate with autosomal dominant hearing loss (Street 2004, Luije ndijk 2004, Bolz 2004, Liu 1997, Sun 2011, Sang 2013). While the underlying mech anism is unknown, these missense variants are primarily located within the conse rved motor domain, which is the same domain impacted by the p.Asp218Asn variant. In summary, although additional studies are required to fully establish its cli nical significance, the p.Asp218Asn variant is likely pathogenic for autosomal d ominant nonsyndromic hearing loss. ACMG/AMP criteria applied: PM1_Strong, PM2_Su pporting, PM3
Invitae RCV000822163 SCV000962954 likely pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 218 of the MYO7A protein (p.Asp218Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs201539845, ExAC 0.02%). This variant has been observed in individuals with autosomal dominant non-syndromic hearing loss (PMID: 21150918, 27911912). It has also been shown to segregate with disease in an extended family (PMID: 21150918). ClinVar contains an entry for this variant (Variation ID: 29924). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000022815 SCV000044104 pathogenic Deafness, autosomal dominant 11 2011-01-01 no assertion criteria provided literature only

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