ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.3527G>A (p.Ser1176Asn) (rs373147966)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171544 SCV001334330 uncertain significance Usher syndrome 2020-05-20 reviewed by expert panel curation The c.3527G>A (p.Ser1176Asn) variant in MYO7A was present in 0.057% (lower bound of the 95% CI of 33/42036) of African alleles in gnomAD v3 (BS1_Supporting not met). It has been observed in at least 3 individuals with Usher syndrome type 1. However, in one proband the p.Ser1176Asn variant was observed in cis with another pathogenic/likely pathogenic variant in MYO7A (BP2; PMID: 26969326). The remaining probands did not have other pathogenic or likely pathogenic variants in MYO7A identified (PM3 and PP4 not met; PMID: 27344577, 27460420, 31479088). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BP2.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724054 SCV000228596 uncertain significance not provided 2014-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000176841 SCV000714448 likely benign not specified 2017-12-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000665185 SCV000789259 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2017-01-20 criteria provided, single submitter clinical testing
Mendelics RCV000988610 SCV001138389 likely pathogenic Usher syndrome type 1 2020-04-17 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073919 SCV001239484 uncertain significance Retinal dystrophy 2018-06-19 criteria provided, single submitter clinical testing
Invitae RCV000724054 SCV001418817 uncertain significance not provided 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1176 of the MYO7A protein (p.Ser1176Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs373147966, ExAC 0.07%). This variant has been observed in several individuals affected with MYO7A-related conditions (PMID: 27460420, 27344577). ClinVar contains an entry for this variant (Variation ID: 196099). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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