Submissions for variant NM_000257.4(MYH7):c.3235C>T (p.Arg1079Trp)

gnomAD frequency: 0.00001  dbSNP: rs192722540

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151250	SCV000199151	uncertain significance	not specified	2014-06-26	criteria provided, single submitter	clinical testing	The Arg1079Trp variant in MYH7 has not been reported in individuals with cardiom yopathy but has been detected in 1/200 Chinese chromosomes by the 1000 Genomes P roject (rs192722540). Other variants at this position have been reported (Arg107 9Gly: Girolami 2010, Waldmuller 2011, LMM unpublished data; Arg10479Trp: dbSNP r s192722540), though their significance is unclear. Arginine at position 1079 is not conserved in evolution, though the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, the clinical significance of the Arg1079Trp variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000365939	SCV000386058	likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000269104	SCV000386059	likely benign	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094089	SCV000386060	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV003320107	SCV000386061	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000277463	SCV000386062	likely benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001704089	SCV000530613	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing	Reported in association with sudden cardiac death, HCM, and DCM, though most patients harbored additional cardiogenetic variants (Sanchez et al., 2016; Zhang et al., 2016; Suktitipat et al., 2017; Girolami et al., 2010); Reported in ClinVar as a variant of uncertain significance or a likely benign variant by other clinical laboratories (ClinVar Variant ID# 164304; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23403236, 22763267, 27930701, 27707468, 28704380, 30165862, 20359594)
Invitae	RCV000326571	SCV000623692	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1079 of the MYH7 protein (p.Arg1079Trp). This variant is present in population databases (rs192722540, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 27930701, 28704380, 33996946). ClinVar contains an entry for this variant (Variation ID: 164304). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000627137	SCV000747951	uncertain significance	Primary familial hypertrophic cardiomyopathy	2017-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777762	SCV000913728	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1079 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: 20359594), in an individual affected with dilated cardiomyopathy (PMID: 30165862), and in three individuals affected with sudden unexplained death (PMID: 27707468, 27930701, 28704380). This variant has been identified in 14/251426 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	RCV002444618	SCV002611744	uncertain significance	Cardiovascular phenotype	2021-08-10	criteria provided, single submitter	clinical testing	The p.R1079W variant (also known as c.3235C>T), located in coding exon 23 of the MYH7 gene, results from a C to T substitution at nucleotide position 3235. The arginine at codon 1079 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in sudden unexplained death cohorts and a cardiomyopathy cohort; however, clinical details were limited and additional cardiac-related alterations were identified in some individuals (Zhang L et al. Mayo Clin Proc, 2016 Nov;91:1503-1514; Campuzano O et al. Sports Med, 2017 Oct;47:2101-2115; Suktitipat B et al. PLoS One, 2017 Jul;12:e0180056; Lu C et al. J Transl Med, 2018 08;16:241). This amino acid position is not 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.
Revvity Omics, Revvity	RCV001704089	SCV003817735	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing