rs727503240
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000257.4(MYH7):c.5690G>A(p.Arg1897His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1897C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5690G>A | p.Arg1897His | missense_variant | 39/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.5690G>A | p.Arg1897His | missense_variant | 38/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5690G>A | p.Arg1897His | missense_variant | 39/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251464Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | Identified with a second variant in a patient with Ebstein anomaly and left ventricular noncompaction in the literature (Mazzarotto et al., 2021); Identified in multiple patients with cardiomyopathy in the literature (Lopes et al., 2015; Hou et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27532257, 35284542, 31983221, 31980526, 25351510, 33500567) - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 12, 2022 | This missense variant replaces arginine with histidine at codon 1897 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 (PMID: 25351510, 27532257), four individuals affected with left ventricular non-compaction (PMID: 33500567, ClinVar SCV001430834.1), and five individuals affected with dilated cardiomyopathy (PMID: 30847666, 31983221, 35284542, ClinVar SCV001430834.1). This variant has been identified in 1/251464 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 05, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Left ventricular noncompaction cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Jan 06, 2020 | 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'. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1897 of the MYH7 protein (p.Arg1897His). This variant is present in population databases (rs727503240, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy, left ventricular noncompaction (PMID: 25351510, 27532257, 31983221, 33500567; Invitae). ClinVar contains an entry for this variant (Variation ID: 164264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2022 | The p.R1897H variant (also known as c.5690G>A), located in coding exon 37 of the MYH7 gene, results from a G to A substitution at nucleotide position 5690. The arginine at codon 1897 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in a variety of cardiomyopathy cohorts, including individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC); however, some individuals had co-occurring variants, and clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 02;19:192-203; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Mazzarotto F et al. Circulation, 2020 02;141:387-398; Hou YC et al. Proc Natl Acad Sci U S A, 2020 02;117:3053-3062; Harper AR et al. Nat Genet, 2021 02;53:135-142; Mazzarotto F et al. Genet Med, 2021 05;23:856-864). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at