Submissions for variant NM_002471.4(MYH6):c.531-19T>A

gnomAD frequency: 0.00045  dbSNP: rs374174532

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000610833	SCV000724480	likely benign	not specified	2017-11-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000610833	SCV001432071	benign	not specified	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.531-19T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 3 acceptor site. Two predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 282696 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 40 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 found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.531-19T>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002064155	SCV002375137	likely benign	Hypertrophic cardiomyopathy 14	2024-01-25	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001726263	SCV005211396	likely benign	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV000610833	SCV001922193	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726263	SCV001963213	likely benign	not provided		no assertion criteria provided	clinical testing