ClinVar Miner

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

gnomAD frequency: 0.00026  dbSNP: rs373147966
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Total submissions: 10
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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.
Eurofins Ntd Llc (ga) RCV000724054 SCV000228596 uncertain significance not provided 2014-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000724054 SCV000714448 likely benign not provided 2020-08-14 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26969326, 31479088, 27460420, 27344577, 33297549)
Counsyl RCV000665185 SCV000789259 uncertain significance Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 2017-01-20 criteria provided, single submitter clinical testing
Mendelics RCV000988610 SCV001138389 uncertain significance Usher syndrome type 1 2023-04-21 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073919 SCV001239484 uncertain significance Retinal dystrophy 2018-06-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000724054 SCV001418817 benign not provided 2024-01-11 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002500491 SCV002791084 uncertain significance Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 2022-03-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689655 SCV005185050 uncertain significance not specified 2024-05-22 criteria provided, single submitter clinical testing Variant summary: MYO7A c.3527G>A (p.Ser1176Asn) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 248872 control chromosomes (gnomAD). c.3527G>A has been reported in the literature in heterozygous or presumed compound heterozygous state individuals affected with MYO7A-Related Disorders (example: Bonnet_2016, Garcia-Garcia_2020, Yan_2016, Sloan-Heggen_2016). In at-least one of these individuals second pathogenic variant (MYO7A c.6487G>A, p.Gly2163Ser) was reported in homozygous state, providing supporting evidence for a benign role (Sloan-Heggen_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27460420, 33297549, 26969326, 27344577). ClinVar contains an entry for this variant (Variation ID: 196099). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences RCV004734791 SCV005344301 uncertain significance MYO7A-related disorder 2024-08-21 no assertion criteria provided clinical testing The MYO7A c.3527G>A variant is predicted to result in the amino acid substitution p.Ser1176Asn. This variant was reported in homozygous or heterozygous state, along with additional MYO7A variant(s), in individuals with MYO7A-related disorders (Sloan-Heggen et al. 2016. PubMed ID: 26969326, Bonnet et al. 2016. PubMed ID: 27460420; Khateb et al. 2020. PubMed ID: 31479088; García-García et al. 2020. PubMed ID: 33297549, Yan et al. 2016. PubMed ID: 27344577). This variant is reported in 0.066% of alleles in individuals of African descent in gnomAD. This variant is interpreted as uncertain significance by the ClinGen Hearing Loss Variant Curation Expert Panel in ClinVar (ClinVar ID: 196099). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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