Submissions for variant NM_000257.4(MYH7):c.4481A>T (p.His1494Leu)

gnomAD frequency: 0.00001  dbSNP: rs727505329

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156875	SCV000206596	uncertain significance	not specified	2015-06-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.His1494Leu va riant in MYH7 has been identified in 1 Caucasian infant with infantile-onset DCM and 1 individual with HCM (LMM unpublished data, Berge 2014). This variant has been identified in 2/66740 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs727505329). The p.His1494Leu variant was predicted to be benign using a computational tool clinically validat ed by our laboratory. This tool's benign prediction is estimated to be correct 8 9% of the time (Jordan 2011). In summary, while the clinical significance of the p.His1494Leu variant is uncertain, these data suggest that it is more likely to be benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170991	SCV001333657	uncertain significance	Cardiomyopathy	2018-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170991	SCV001342146	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 1494 of the MYH7 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID 24111713). This variant has been identified in 2/282874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001320219	SCV001510996	uncertain significance	Hypertrophic cardiomyopathy	2022-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1494 of the MYH7 protein (p.His1494Leu). This variant is present in population databases (rs727505329, gnomAD 0.002%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713). ClinVar contains an entry for this variant (Variation ID: 180072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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.
Revvity Omics, Revvity	RCV003133154	SCV003817721	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV003133154	SCV003852899	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy (Berge et al., 2014; Stava et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35653365, 34542152, 24111713)