Submissions for variant NM_000257.4(MYH7):c.5562G>A (p.Thr1854=)

gnomAD frequency: 0.00015  dbSNP: rs368706722

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035970	SCV000059622	likely benign	not specified	2012-08-02	criteria provided, single submitter	clinical testing	p.Thr1854Thr in exon 38 of MYH7: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 2/8600 European A merican chromosomes from a broad population by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS).
GeneDx	RCV000035970	SCV000519077	benign	not specified	2015-10-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080595	SCV000623746	likely benign	Hypertrophic cardiomyopathy	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617785	SCV000736124	likely benign	Cardiovascular phenotype	2017-11-29	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.
Color Diagnostics, LLC DBA Color Health	RCV000777750	SCV000913712	likely benign	Cardiomyopathy	2018-08-25	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000786174	SCV005211406	likely benign	not provided		criteria provided, single submitter	not provided
Blueprint Genetics	RCV000157366	SCV000207104	likely benign	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786174	SCV000924880	uncertain significance	not provided	2017-06-12	no assertion criteria provided	provider interpretation	p.Thr1854Thr (c.5562G>A (silent); chr14:23883309 ) in the MYH7 gene (NM_000257.3) Given that there are no strong case reports available for this variant and that this variant is present at a high frequency in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is present in ClinVar and is classified as a variant of uncertain significance by one lab, a likely benign variant by two labs and a benign variant by the final lab. This variant may have been reported in the literature, although it is unclear. This is a weak case, as the paper states that two variants were found in 2 individuals with HCM: MYBPC3 IVS14-23G>A in combination with "MYH7 T1854 mol/L." I am unclear if the mol/L is a typo. It is not mentioned again in the paper. It is classified as a disease-causing mutation based on in silico analysis (Page et al 2012). This residue is not enriched in cases vs controls (Homburger et al 2016, amr et al 2016). Per the test report, "Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies." The threonine at codon 1854 is moderately conserved across species, whereas neighboring amino acids are strongly conserved. Another variant at this codon (p.Thr8154Met) is classified as follows in Clinvar (#= number of labs): pathogenic (1) likely pathogenic (1) and as a VUS (2). A nearby variant (p.Glu1856Lys), is reported to be pathogenic for Liang distal myopathy type 1; however, it has not been classified by any clinical labs. The variant was reported online in 34 of 137,831 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 31 of 63,301 individuals of European descent (MAF=0.02%), 3 of 17,206 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
PreventionGenetics, part of Exact Sciences	RCV004534750	SCV004747820	likely benign	MYH7-related disorder	2020-10-08	no assertion criteria provided	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).