Submissions for variant NM_000257.4(MYH7):c.5495G>A (p.Arg1832His)

gnomAD frequency: 0.00004  dbSNP: rs730880820

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158704	SCV000208639	uncertain significance	not provided	2019-05-31	criteria provided, single submitter	clinical testing	Reported in two brothers with LVNC and skeletal myopathy (Moore and Batlivala, 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Color Diagnostics, LLC DBA Color Health	RCV001182256	SCV001347646	uncertain significance	Cardiomyopathy	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1832 of the MYH7 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 33495597). It has also been reported in one individual affected with dilated cardiomyopathy who also carried a pathogenic TTN truncation variant (PMID: 34935411). Additionally, this variant has been reported in one individual affected with left ventricular non-compaction (DOI:10.1016/j.ihjccr.2018.03.003). This variant has been identified in 7/250740 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	RCV001202688	SCV001373811	uncertain significance	Hypertrophic cardiomyopathy	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1832 of the MYH7 protein (p.Arg1832His). This variant is present in population databases (rs730880820, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or early-onset myopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 181283). 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.
Revvity Omics, Revvity	RCV000158704	SCV003817715	uncertain significance	not provided	2019-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298184	SCV003993396	uncertain significance	Cardiovascular phenotype	2023-05-05	criteria provided, single submitter	clinical testing	The p.R1832H variant (also known as c.5495G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5495. The arginine at codon 1832 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a pediatric dilated cardiomyopathy (DCM) cohort; however, clinical details were limited and additional alterations in other cardiac-related genes were identified in this case (Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854). 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.