Submissions for variant NM_000257.4(MYH7):c.5066G>A (p.Arg1689His)

gnomAD frequency: 0.00001  dbSNP: rs772008016

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000620900	SCV000737139	uncertain significance	Cardiovascular phenotype	2016-07-26	criteria provided, single submitter	clinical testing	The p.R1689H variant (also known as c.5066G>A), located in coding exon 33 of the MYH7 gene, results from a G to A substitution at nucleotide position 5066. The arginine at codon 1689 is replaced by histidine, an amino acid with highly similar properties. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (2/106202). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628878	SCV000749786	uncertain significance	Hypertrophic cardiomyopathy	2023-08-04	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs772008016, gnomAD 0.005%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 519115). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28356264). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1689 of the MYH7 protein (p.Arg1689His).
Color Diagnostics, LLC DBA Color Health	RCV001186063	SCV001352401	uncertain significance	Cardiomyopathy	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1689 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 an individual affected with hypertrophic cardiomyopathy (PMID: 28356264). This variant has been identified in 5/282720 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.
GeneDx	RCV001775923	SCV002012798	uncertain significance	not provided	2021-10-08	criteria provided, single submitter	clinical testing	Identified in a patient with hypertrophic cardiomyopathy; however, this patient also harbored an additional cardiogenetic variant (Gomez et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 519115; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek 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: 28356264, 21310275)
Fulgent Genetics, Fulgent Genetics	RCV002483712	SCV002780253	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	2021-08-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001186063	SCV004826560	uncertain significance	Cardiomyopathy	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1689 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 an individual affected with hypertrophic cardiomyopathy (PMID: 28356264). This variant has been identified in 5/282720 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.