Submissions for variant NM_000257.4(MYH7):c.5761C>T (p.Arg1921Trp)

dbSNP: rs539290591

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158717	SCV000208652	uncertain significance	not provided	2016-11-08	criteria provided, single submitter	clinical testing	p.Arg1921Trp (CGG>TGG): c.5761 C>T in exon 39 of the MYH7 gene (NM_000257.2). The R1921W variant in the MYH7 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. The R1921W variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The R1921 residue is conserved across species. In silico analysis predicts R1921W is damaging the protein structure/function. Mutations in nearby residues (E1914K, R1925G, I1927F, T1929M) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the R1921W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while R1921W is a good candidate for a pathogenic variant, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant.
Invitae	RCV000704962	SCV000833937	uncertain significance	Hypertrophic cardiomyopathy	2024-01-30	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 1921 of the MYH7 protein (p.Arg1921Trp). This variant is present in population databases (rs539290591, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221, 36252119). ClinVar contains an entry for this variant (Variation ID: 181291). 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%. This variant disrupts the p.Arg1921 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32746448; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV001181613	SCV001346794	uncertain significance	Cardiomyopathy	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1921 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 2/251376 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000158717	SCV002502340	uncertain significance	not provided	2021-09-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354390	SCV002650735	uncertain significance	Cardiovascular phenotype	2021-05-12	criteria provided, single submitter	clinical testing	The p.R1921W variant (also known as c.5761C>T), located in coding exon 37 of the MYH7 gene, results from a C to T substitution at nucleotide position 5761. The arginine at codon 1921 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Mazzarotto F et al. Circulation, 2020 02;141:387-398). 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.
Revvity Omics, Revvity	RCV000158717	SCV003817666	uncertain significance	not provided	2020-03-16	criteria provided, single submitter	clinical testing