Submissions for variant NM_000257.4(MYH7):c.2168G>A (p.Arg723His)

gnomAD frequency: 0.00001  dbSNP: rs397516135

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035773	SCV000059424	uncertain significance	not specified	2014-04-04	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628894	SCV000749802	likely pathogenic	Hypertrophic cardiomyopathy	2022-11-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg723 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430197, 9829907, 11113006, 17097032, 19651039, 20819418, 23318932, 25935763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 42886). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25935763). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 723 of the MYH7 protein (p.Arg723His).
CeGaT Center for Human Genetics Tuebingen	RCV001092198	SCV001248601	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110427	SCV001267864	uncertain significance	Dilated cardiomyopathy 1S	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001110428	SCV001267865	uncertain significance	MYH7-related skeletal myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV003320052	SCV001267866	uncertain significance	Myosin storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002415463	SCV002724739	uncertain significance	Cardiovascular phenotype	2021-11-15	criteria provided, single submitter	clinical testing	The p.R723H variant (also known as c.2168G>A), located in coding exon 18 of the MYH7 gene, results from a G to A substitution at nucleotide position 2168. The arginine at codon 723 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in a cardiac genetic testing cohort in an individual noted to have hypertrophic cardiomyopathy with limited clinical details (García-Giustiniani D et al. Heart, 2015 Jul;101:1047-53). 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.
Revvity Omics, Revvity	RCV001092198	SCV003817729	uncertain significance	not provided	2021-12-21	criteria provided, single submitter	clinical testing
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology	RCV000148962	SCV000154211	pathogenic	Familial cardiomyopathy		no assertion criteria provided	not provided	Converted during submission to Pathogenic.