Submissions for variant NM_000257.4(MYH7):c.5065C>T (p.Arg1689Cys)

gnomAD frequency: 0.00001  dbSNP: rs730880915

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721011	SCV000208805	uncertain significance	not provided	2021-03-18	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 181394; Landrum 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: 32163302)
Invitae	RCV000693933	SCV000822356	uncertain significance	Hypertrophic cardiomyopathy	2022-06-05	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 1689 of the MYH7 protein (p.Arg1689Cys). This variant is present in population databases (rs730880915, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181394). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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	RCV001185248	SCV001351421	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1689 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 an individual affected with hypertrophic cardiomyopathy (PMID: 32163302, 33495597). This variant has been identified in 6/282678 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.
Fulgent Genetics, Fulgent Genetics	RCV002478480	SCV002790918	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	2022-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372630	SCV004083060	uncertain significance	Cardiovascular phenotype	2023-08-18	criteria provided, single submitter	clinical testing	The p.R1689C variant (also known as c.5065C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5065. The arginine at codon 1689 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with an MYBPC3 variant in an individual from a hypertrophic cardiomyopathy cohort (Harper AR et al. Circ Genom Precis Med, 2020 Jun;13:e002783). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.