Submissions for variant NM_000260.4(MYO7A):c.4039C>T (p.Arg1347Cys)

gnomAD frequency: 0.00002  dbSNP: rs111534474

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000369577	SCV000374362	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000277269	SCV000374363	uncertain significance	Usher syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000330024	SCV000374364	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859830	SCV002121561	pathogenic	not provided	2024-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1347 of the MYO7A protein (p.Arg1347Cys). This variant is present in population databases (rs111534474, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive MYO7A-related conditions (Invitae). 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: 306185). 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%. This variant disrupts the p.Arg1347 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002487363	SCV002782658	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2021-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317189	SCV004020527	uncertain significance	not specified	2023-06-22	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.4039C>T (p.Arg1347Cys) results in a non-conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4039C>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A different missense variant affecting the same codon (c.4039C>A, p.Arg1347Ser, HGMD CM1413380) has been described as disease causing, although it is not known if this amino acid residue is clinically significant. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Rare Diseases, West China Hospital, Sichuan University	RCV000369577	SCV005687059	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2025-01-09	criteria provided, single submitter	research	PM3;PM5;PM2_Supporting;PP3