Submissions for variant NM_000257.4(MYH7):c.4423C>T (p.Arg1475Cys)

gnomAD frequency: 0.00009  dbSNP: rs139646545

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000515035	SCV000208592	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing	Reported in individuals with HCM; however, the variant did not segregate with disease in at least one affected family member (Hougs et al., 2005; Kindel et al., 2012; Andreasen et al., 2013; Miller et al., 2013; Berge et al., 2014); Identified in one individual with borderline ARVC (Medeiros-Domingo et al., 2016); 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: 23299917, 19035361, 24111713, 22555271, 33232181, 23054336, 15483641, 27194543, 34542152)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000515035	SCV000609668	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000628837	SCV000749744	uncertain significance	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1475 of the MYH7 protein (p.Arg1475Cys). This variant is present in population databases (rs139646545, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic or arrhythmogenic right ventricular cardiomyopathy (PMID: 15483641, 22555271, 24111713, 33232181, 35653365). ClinVar contains an entry for this variant (Variation ID: 181256). 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.
Blueprint Genetics	RCV000515035	SCV000927201	uncertain significance	not provided	2017-03-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181612	SCV001346793	uncertain significance	Cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1475 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15483641, 22555271, 23054336, 24111713), in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27194543), and in one individual affected with noncompaction cardiomyopathy (PMID: 30847666). This variant has been identified in 13/282862 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	RCV002326903	SCV002631170	uncertain significance	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The p.R1475C variant (also known as c.4423C>T), located in coding exon 30 of the MYH7 gene, results from a C to T substitution at nucleotide position 4423. The arginine at codon 1475 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals in several cardiomyopathy and arrhythmia genetic testing cohorts; however, clinical details were limited, and additional cardiac variants were detected in some cases (Hougs L et al. Eur J Hum Genet, 2005 Feb;13:161-5; Kindel SJ et al. J Card Fail, 2012 May;18:396-403; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Medeiros-Domingo A et al. Europace, 2017 Jun;19:1063-1069; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28). This alteration was also reported in a biobank cohort (Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002484977	SCV002792971	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-08-09	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000515035	SCV001798368	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000515035	SCV001919685	likely benign	not provided		no assertion criteria provided	clinical testing