Submissions for variant NM_004999.4(MYO6):c.188-3T>C

gnomAD frequency: 0.00017  dbSNP: rs373199401

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218607	SCV000270539	likely benign	not specified	2015-02-06	criteria provided, single submitter	clinical testing	c.188-3T>C in intron 3 of MYO6: This variant is not expected to have clinical si gnificance because it does not cause the splice site sequence to diverge from co nsensus. It has been identified in 15/67345 European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373199401).
Illumina Laboratory Services, Illumina	RCV000322634	SCV000465354	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	RCV000379547	SCV000465355	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.
GeneDx	RCV001574138	SCV001800899	likely benign	not provided	2020-12-21	criteria provided, single submitter	clinical testing
Invitae	RCV001574138	SCV002226551	uncertain significance	not provided	2022-09-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MYO6-related conditions. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 227673). This variant is present in population databases (rs373199401, gnomAD 0.03%). This sequence change falls in intron 3 of the MYO6 gene. It does not directly change the encoded amino acid sequence of the MYO6 protein. It affects a nucleotide within the consensus splice site.
AiLife Diagnostics, AiLife Diagnostics	RCV001574138	SCV002501761	uncertain significance	not provided	2021-07-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937833	SCV004751299	likely benign	MYO6-related condition	2019-06-06	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).