Submissions for variant NM_000257.4(MYH7):c.3341G>A (p.Arg1114His)

gnomAD frequency: 0.00001  dbSNP: rs730880773

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158604	SCV000208539	likely pathogenic	not provided	2012-02-27	criteria provided, single submitter	clinical testing	The Arg1114His variant has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Arg1114His results in a conservative amino acid substitution of a positively charged Arginine with a positively charged Histidine at a position that is conserved across species. In silico analysis predicts Arg1114His to be probably damaging to protein structure or function. A mutation in a nearby codon (Glu1116Lys) has been reported in associated with HCM, further supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Arg1114His was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Arg1114His is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant with the clinical and molecular information available at this time. The variant is found in HCM panel(s).
Invitae	RCV001344619	SCV001538683	uncertain significance	Hypertrophic cardiomyopathy	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1114 of the MYH7 protein (p.Arg1114His). This variant is present in population databases (rs730880773, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181221). 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. 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	RCV003531996	SCV004356877	uncertain significance	Cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1114 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 two individuals affected with hypertrophic cardiomyopathy (Pham 2022, DOI: 10.2174/18741924-v16-e2202280 and PMID: 27532257) and in an individual affected with sudden unexplained death (PMID: 27707468). This variant has been identified in 3/244126 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.