Submissions for variant NM_002471.4(MYH6):c.1132G>A (p.Gly378Ser)

gnomAD frequency: 0.00014  dbSNP: rs148962966

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154766	SCV000204446	likely benign	not specified	2013-12-26	criteria provided, single submitter	clinical testing	Gly378Ser in exon 12 of MYH6: This variant is not expected to have clinical sign ificance because it has been identified in 1.0% (6/572) of Asian chromosomes by the 1000 Genomes Project (dbSNP rs148962966). Gly378Ser in exon 12 of MYH6 (rs1 48962966; allele frequency = 1.0%, 6/572)
Ambry Genetics	RCV000241733	SCV000319653	likely benign	Cardiovascular phenotype	2017-12-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000464311	SCV000557903	benign	Hypertrophic cardiomyopathy 14	2024-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001697081	SCV000718668	likely benign	not provided	2021-05-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170246	SCV001332806	likely benign	Cardiomyopathy	2017-12-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154766	SCV001432004	benign	not specified	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.1132G>A (p.Gly378Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 251172 control chromosomes, including 1 homozygote (gnomAD). The variant was found at a frequency of 0.006 within the East Asian subpopulation, this frequency is approximately 230-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.1132G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Genetics and Genomics Program, Sidra Medicine	RCV001293155	SCV001434152	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Genetics and Genomics Program, Sidra Medicine	RCV001293167	SCV001434164	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Clinical Genetics, Academic Medical Center	RCV000154766	SCV001925762	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001697081	SCV001973843	likely benign	not provided		no assertion criteria provided	clinical testing