Submissions for variant NM_004999.4(MYO6):c.2836C>T (p.Arg946Cys)

gnomAD frequency: 0.00039  dbSNP: rs141845119

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000710324	SCV000840512	likely benign	Nonsyndromic genetic hearing loss	2018-09-28	reviewed by expert panel	curation	The filtering allele frequency of the p.Arg946Cys variant in the MYO6 gene is 0.095% (39/30776) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (BS1).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151470	SCV000199525	uncertain significance	not specified	2013-08-16	criteria provided, single submitter	clinical testing	The Arg946Cys variant in MYO6 has not been reported in individuals with hearing loss, but has been identified in 0.04% (4/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141845119). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Computational anal yses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant cannot be determined with ce rtainty.
Eurofins Ntd Llc (ga)	RCV000487698	SCV000228363	uncertain significance	not provided	2015-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487698	SCV000575489	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000487698	SCV001021842	likely benign	not provided	2023-11-20	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000487698	SCV001144694	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001162537	SCV001324493	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	RCV001162538	SCV001324494	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000487698	SCV001790778	likely benign	not provided	2020-10-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27068579)
PreventionGenetics, part of Exact Sciences	RCV003935273	SCV004761824	likely benign	MYO6-related condition	2019-10-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487698	SCV001953362	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487698	SCV001975416	likely benign	not provided		no assertion criteria provided	clinical testing