Submissions for variant NM_000257.4(MYH7):c.4679G>A (p.Arg1560Gln)

gnomAD frequency: 0.00001  dbSNP: rs730880806

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766461	SCV000208601	uncertain significance	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Homburger et al., 2016); however, this variant lacks observation in significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity; 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: 27247418)
Invitae	RCV000628848	SCV000749755	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1560 of the MYH7 protein (p.Arg1560Gln). This variant is present in population databases (rs730880806, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181262). 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.Arg1560 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30166250). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV000778009	SCV000914118	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1560 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: 27247418). This variant has been identified in 4/282352 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	RCV000766461	SCV002502483	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326904	SCV002634429	uncertain significance	Cardiovascular phenotype	2021-07-28	criteria provided, single submitter	clinical testing	The p.R1560Q variant (also known as c.4679G>A), located in coding exon 32 of the MYH7 gene, results from a G to A substitution at nucleotide position 4679. The arginine at codon 1560 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6). 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.
Fulgent Genetics, Fulgent Genetics	RCV002492626	SCV002783512	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	2022-04-07	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158666	SCV000280354	uncertain significance	not specified	2013-01-07	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg1560Gln (R1560Q; c.4679 G>A) in the MYH7 gene. We classify it as a variant of unknown significance as well. This variant is completely novel and has not previously been reported in individuals with HCM. There is no published segregation data. Variation at one nearby residue has been reported in the HGMD to be associated with HCM: Glu1555Lys. This may support the functional importance of this region of the protein. This is a non-conservative amino acid change, resulting in the replacement of an arginine (basic) with a glutamine (polar). Arginine at this location is 100% conserved across 9 mammalian species. The adjacent residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Possibly Damaging” with a score of 0.562. This variant has not been seen in ~6500 individuals from publicly available population datasets as of January 24, 2014. It is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this codon listed in 1000 Genomes or dbSNP.