Submissions for variant NM_000257.4(MYH7):c.4031G>A (p.Arg1344Gln)

gnomAD frequency: 0.00002  dbSNP: rs797045097

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211873	SCV000245640	uncertain significance	not specified	2019-08-12	criteria provided, single submitter	clinical testing	The p.Arg1344Gln variant in MYH7 has been reported in at least 3 individuals with HCM (Marsiglia 2013, Bos 2014, Cirino 2017, LMM data). It was also identified in 4/282350 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID #208597). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, PP3.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000190606	SCV000256119	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179058	SCV001343639	uncertain significance	Cardiomyopathy	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1344 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 four unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 24793961, 25558701, 29030401, 32894683), in an individual affected with left ventricular noncompaction (PMID: 34853230), and in an individual affected with sudden unexplained death (PMID: 31195250). This variant has been identified in 4/282350 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.
Invitae	RCV001852531	SCV002246627	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-19	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 1344 of the MYH7 protein (p.Arg1344Gln). This variant is present in population databases (rs797045097, gnomAD 0.005%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24093860, 24793961, 25558701, 27247418, 29030401, 32528171, 32894683). ClinVar contains an entry for this variant (Variation ID: 208597). 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%. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000223729	SCV002502482	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354537	SCV002622373	uncertain significance	Cardiovascular phenotype	2019-12-02	criteria provided, single submitter	clinical testing	The p.R1344Q variant (also known as c.4031G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4031. The arginine at codon 1344 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) as well as once in a sudden unexplained death (SUD) cohort (Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Arad M et al. Isr. Med. Assoc. J., 2014 Nov;16:707-13; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10:; Gando I et al. Forensic Sci. Int., 2019 Aug;301:289-298). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000223729	SCV004702049	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MYH7: PM1, PP3, PS4:Supporting
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223729	SCV000280344	likely pathogenic	not provided	2011-11-03	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.Arg1344Gln (c.4031G>A) in the MYH7 gene. Given the newly reported presence in cases around the world, the absence in unselected populations, we consider this variant likely disease causing. When the patient first had genetic testing the variant was novel, with no published data. Ackerman's group observed the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2005). Arad et al (2014) reported the variant in a patient with HCM in their Israeli cohort. The patient presented at 13yo and had "massive LVH" (also described as "severe distal hypertrophy"), severe heart failure, and, reportedly, growth delay. It is unclear what genes were sequenced. Marsiglia et al (2013) observed the variant in one of 268 unrelated patients with HCM in their Brazilian cohort. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2. There is no ClinVar entry (as of July 22nd, 2015) and there are no other cases in SHaRe. In silico analysis with Polyphen predicts this variant as probably damaging with a score of 0.984. MutationTaster predicts this variant to be disease causing with a score of 43. The Arganine at codon 1344 is completely conserved across species and isoforms. A polar positive Arginine is replaced with a polar neutral Glutamine. Another variant, p.Arg1344Trp has been reported with disease and is in ClinVar as pathogenic by GeneDx and a variant of uncertain significance by LMM. The variant is not listed in dbSNP or 1000 genomes (as of June 20, 2013). The variant is also not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,500 Caucasian and African American individuals (as of June 20, 2013). Bos et al (2014) did not observe the variant in 200 "ostensibly healthy" individuals. This variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). However, another variant at that codon (p.Arg1344Trp) is present in 2 of 60,278 individuals.