ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.5648G>A (p.Arg1883Gln)

gnomAD frequency: 0.00004  dbSNP: rs111033215
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Total submissions: 13
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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 RCV000844722 SCV000059851 pathogenic Rare genetic deafness 2018-06-26 criteria provided, single submitter clinical testing The p.Arg1883Gln variant in MYO7A has been reported in 4 individuals with Usher Syndrome Type I (USH1), all of whom also carried a second pathogenic variant (Ou yang 2005, Nakanishi 2010, Bonnet 2011, Le Quesne Stabej 2012, Jacobson 2011). T he p.Arg1883Gln variant has been identified in 0.0088% (3/34194) Latino chromoso mes and 0.004% (10/274046) of total chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033215). Although this variant has been seen in the general population, its overall frequency is low en ough to be consistent with a recessive carrier frequency. Computational predicti on tools and conservation analysis suggest that the p.Arg1883Gln variant may imp act the protein. In summary, this variant meets criteria to be classified as pat hogenic for autosomal recessive Usher syndrome based upon multiple occurrences a s a compound heterozygous variant with pathogenic variants in the same gene in i ndividuals with Usher syndrome, low frequency in the gnomAD database, and predic ted impact on protein. ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supportin g, PP3, PP4.
GeneDx RCV000413954 SCV000490900 pathogenic not provided 2023-10-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22135276, 24199935, 15660226, 20844544, 21569298, 25714468, 21873662, 16963483, 31266775, 33576163)
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000036199 SCV000891609 likely pathogenic Usher syndrome type 1 2017-12-30 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV000413954 SCV000964064 pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1883 of the MYO7A protein (p.Arg1883Gln). This variant is present in population databases (rs111033215, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 20844544, 21569298, 21873662, 22135276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43294). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000413954 SCV001446991 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV004814949 SCV005068583 pathogenic Retinal dystrophy 2021-01-01 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000036199 SCV005374822 pathogenic Usher syndrome type 1 criteria provided, single submitter clinical testing The observed missense c.5648G>A(p.Arg1883Gln) variant in MYO7A gene has been reported previously in compound heterozygous state in multiple individuals affected with Usher syndrome (Le Quesne Stabej P, et al., 2012; Jacobson SG, et al., 2011; Bonnet C, et al., 2011; Ouyang XM, et al., 2005). The p.Arg1883Gln variant has been reported with allele frequency of 0.003% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on MYO7A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 1883 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. The same variant in MYO7A gene has been identified in heterozygous state in sibling and paternal cousin
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782029 SCV005395141 pathogenic Usher syndrome 2024-09-09 criteria provided, single submitter clinical testing Variant summary: MYO7A c.5648G>A (p.Arg1883Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245768 control chromosomes. c.5648G>A has been reported in the literature in multiple individuals affected with Usher Syndrome. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27460420, 30459346, 36484953, 15660226, 22135276). ClinVar contains an entry for this variant (Variation ID: 43294). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005007945 SCV005629477 pathogenic Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 2024-01-22 criteria provided, single submitter clinical testing
Counsyl RCV000983988 SCV000797165 likely pathogenic Autosomal recessive nonsyndromic hearing loss 2 2018-01-16 no assertion criteria provided clinical testing
Natera, Inc. RCV001273516 SCV001456627 pathogenic Usher syndrome type 1B 2020-09-16 no assertion criteria provided clinical testing
Refractive Surgery Department, Bright Eye Hospital RCV000036199 SCV002508889 likely pathogenic Usher syndrome type 1 2022-05-13 no assertion criteria provided clinical testing WES identified two novel compound heterozygous mutations (c.5648G>A(rs111033215) and c.6238-1G>C) in MYO7A in two patients with Usher syndrome type 1. We found that the mutation c.5648G>A was predicted as “Probably Damaging” by the PolyPhen2 analysis. It was also evaluated as “Deleterious” and “Disease Causing” by other prediction programs (SIFT, PROVEIN, MutationTaster). Thus, the mutation of c.5648G>A was potentially pathogenic.
PreventionGenetics, part of Exact Sciences RCV004734547 SCV005351120 pathogenic MYO7A-related disorder 2024-09-16 no assertion criteria provided clinical testing The MYO7A c.5648G>A variant is predicted to result in the amino acid substitution p.Arg1883Gln. This variant has been reported in individuals with features consistent with Usher syndrome, along with a second MYO7A variant (see for example: Ouyang et al. 2005. PubMed ID: 15660226; Table S2, Galbis-Martínez. 2021. PubMed ID: 33576163; Table S1, Lin. 2024. PubMed ID: 38219857). This variant was present in two related individuals in the compound heterozygous state, and the variants were present in heterozygous states in unaffected family members (Lin. 2022. PubMed ID: 36484953). This variant is reported in 0.0086% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.

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