Submissions for variant NM_000257.4(MYH7):c.3777C>T (p.His1259=)

gnomAD frequency: 0.00054  dbSNP: rs149103761

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758030	SCV000564483	benign	Cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The filtering allele frequency of the c.3777C>T (p.His1259=) variant in the MYH7 gene is 0.14% (22/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035867	SCV000059518	likely benign	not specified	2011-11-14	criteria provided, single submitter	clinical testing	His1259His in exon 28 of MYH7: This variant has been reported in the SNP databas e (rs149103761; allele frequency = n/a). It does not change an amino acid and do es not affect the splice consensus sequence. This makes a disease causing role v ery unlikely. His1259His in exon 28 of MYH7 (rs149103761; allele frequency = n/ a)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086412	SCV000623704	benign	Hypertrophic cardiomyopathy	2025-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589190	SCV000696349	likely benign	not provided	2017-06-26	criteria provided, single submitter	clinical testing	Variant summary: The MYH7 c.3777C>T (p.His1259His) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 23/121404 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.002114 (22/10406). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MYH7 variant (0.0012508), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign and one lab classified it as VUS, all without evidence for independent evaluaiton. Taken together, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000758030	SCV001358222	benign	Cardiomyopathy	2019-02-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000589190	SCV001916065	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362623	SCV002625746	likely benign	Cardiovascular phenotype	2018-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Cohesion Phenomics	RCV001086412	SCV003803695	benign	Hypertrophic cardiomyopathy	2022-09-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000758030	SCV004239461	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000758030	SCV004818015	benign	Cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035867	SCV001925979	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589190	SCV001958178	likely benign	not provided		no assertion criteria provided	clinical testing