ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5690G>A (p.Arg1897His) (rs727503240)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151233 SCV000199101 uncertain significance not specified 2019-08-12 criteria provided, single submitter clinical testing The p.Arg1897His variant in MYH7 has been identified in 2 individuals with HCM and 1 individual with LVNC (Lopes 2015, Walsh 2017, LMM data). It has also been identified in 1/30616 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/) and reported in ClinVar (Variation ID #164264). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting.
GeneDx RCV000158713 SCV000208648 likely pathogenic not provided 2013-11-01 criteria provided, single submitter clinical testing p.Arg1897His (CGC>CAC): c.5690 G>A in exon 39 of the MYH7 gene (NM_000257.2). The Arg1897His variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg1897His results in a conservative amino acid substitution of one positively charged residue for another, the Arg1897 residue is conserved across species. In silico analysis predicts Arg1897His is probably damaging to the protein structure/function. Mutations in nearby residues (His1901Gln, Glu1902Lys) have been reported n association with DCM, further supporting the functional importance of this region of the protein. Furthermore, the Arg1897His variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Arg1897His is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM-CRDM panel(s).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158713 SCV000493624 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Invitae RCV000477566 SCV000546189 uncertain significance Hypertrophic cardiomyopathy 2016-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1897 of the MYH7 protein (p.Arg1897His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 164264). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254747 SCV001430834 uncertain significance Left ventricular noncompaction cardiomyopathy 2020-01-06 no assertion criteria provided research MYH7 Arg1897His has been reported multiple times in patients with varying and mixed phenotypes. It has been reported in at least 2 probands with hypertrophic cardiomyopathy (Walsh R, et al., 2017; Da Rocha Lopes LM, 2015) as well as 1 proband with childhood-onset dilated cardiomyopathy (Genedx, Pers. Comm.). A child with LVNC has been reported to carry this variant and an MYH7 splice variant (Praxis fuer Humangenetik Tuebingen, Pers. Comm.). The Laboratory of Molecular Medicine has identified this variant in a newborn with Epstein's anomoly, atrial septal defect, arrhythmia and LVNC, however they also had an MYH7 nonsense variant (Pers. Comm.). Invitae have identified this variant in a patient with DCM and non-compaction (Pers. Comm.). Finally, we have identified this variant in a proband with LVNC and possible DCM. The proband's child was diagnosed with LVNC and the variant was found to segregate to the child. MYH7 Arg1897His is present at a low frequency in the Genome Aggregation Database (AF= 0.000004; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen2, CADD predict this variant to be deleterious. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is rare in the general population (PM2), has been identified in multiple similar cases (PS4_Moderate) and in silico tools predict it to deleterious (PP3), therefore we classify MYH7 Arg1897His as a variant of 'uncertain significance'.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.