Submissions for variant NM_004999.4(MYO6):c.2818C>T (p.Arg940Cys)

gnomAD frequency: 0.00006  dbSNP: rs200205409

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000314135	SCV000465408	uncertain significance	Autosomal recessive nonsyndromic hearing loss 37	2018-01-12	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	RCV000371172	SCV000465409	uncertain significance	Autosomal dominant nonsyndromic hearing loss 22	2018-01-12	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612094	SCV000711152	uncertain significance	not specified	2017-09-14	criteria provided, single submitter	clinical testing	The p.Arg940Cys variant in MYO6 has not been previously reported in individuals hearing loss, but has been identified in 29/ 126304 of European chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200205409). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analyses suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. In summary, the clinical significance of the p.Arg940Cys variant is uncerta in.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757545	SCV000885809	uncertain significance	not provided	2017-08-25	criteria provided, single submitter	clinical testing	The p.Arg940Cys variant (rs200205409) has not been reported in the medical literature nor has it been previously identified in our laboratory. The p.Arg940Cys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.023% in the non-Finnish European population (identified in 29 out of 126,304 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 357999). The arginine at codon 940 is moderately conserved considering 13 species (Alamut software v2.9), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: damaging, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Arg940Cys variant cannot be determined with certainty.
Invitae	RCV000757545	SCV002316840	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing	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. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 357999). This variant has not been reported in the literature in individuals affected with MYO6-related conditions. This variant is present in population databases (rs200205409, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 940 of the MYO6 protein (p.Arg940Cys).
GeneDx	RCV000757545	SCV002577278	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge