ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs192722540
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Total submissions: 13
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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 Other variants at this position have been reported (Arg107 9Gly: Girolami 2010, Waldmuller 2011, LMM unpublished data; Arg10479Trp: dbSNP r s192722540), though their significance is unclear.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, the in silico prediction for this alteration is inconclusive. 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
All of Us Research Program, National Institutes of Health RCV000777762 SCV004814406 uncertain significance Cardiomyopathy 2023-08-15 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.

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