Submissions for variant NM_000257.4(MYH7):c.5243G>A (p.Cys1748Tyr)

gnomAD frequency: 0.00005  dbSNP: rs200303340

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158688	SCV000208623	uncertain significance	not provided	2018-12-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The C1748Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The C1748Y variant is observed in 6/66738 (0.01%) alleles from individuals of non-Finnish European background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C1748Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000628926	SCV000749834	uncertain significance	Hypertrophic cardiomyopathy	2023-08-02	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 180440). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 34598319). This variant is present in population databases (rs200303340, gnomAD 0.009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1748 of the MYH7 protein (p.Cys1748Tyr).
CeGaT Center for Human Genetics Tuebingen	RCV000158688	SCV001149162	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001111831	SCV001269432	uncertain significance	Dilated cardiomyopathy 1S	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV003320116	SCV001269433	uncertain significance	Myosin storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001112300	SCV001269949	uncertain significance	Hypertrophic cardiomyopathy 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001112301	SCV001269950	benign	MYH7-related skeletal myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV001183749	SCV001349566	uncertain significance	Cardiomyopathy	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 1748 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 34598319). It has also been reported in an individual affected with long QT syndrome and sudden cardiac arrest (PMID: 30403391). This variant has been identified in 14/282884 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.
Ambry Genetics	RCV002336346	SCV002645383	uncertain significance	Cardiovascular phenotype	2022-10-12	criteria provided, single submitter	clinical testing	The p.C1748Y variant (also known as c.5243G>A), located in coding exon 34 of the MYH7 gene, results from a G to A substitution at nucleotide position 5243. The cysteine at codon 1748 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort, a long QT syndrome cohort, and in the Framingham Heart Study cohort; however, details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9; Stpie-Wojno M et al. Pol Arch Intern Med, 2018 12;128:721-730; Filatova EV et al. Mol Genet Genomic Med, 2021 11;9:e1808). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003320115	SCV003924224	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-03-30	criteria provided, single submitter	clinical testing	MYH7 NM_00257.3 exon 36 p.Cys1748Tyr (c.5243G>A): This variant has not been reported in the literature and is present in 0.009% (12/129192) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/14-23884630-C-T). This variant is present in ClinVar (Variation ID:180440). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Blueprint Genetics	RCV000157365	SCV000207103	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2014-05-13	no assertion criteria provided	clinical testing