rs730880856
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):āc.842G>Cā(p.Arg281Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,800 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R281K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.842G>C | p.Arg281Thr | missense_variant | 10/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.842G>C | p.Arg281Thr | missense_variant | 9/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.842G>C | p.Arg281Thr | missense_variant | 10/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2017 | The Arg281Thr variant in the MYH7 gene has been reported in a large family with noncompaction of the ventricular myocardium (NVM). Budde B et al. (2007) reported that the Arg281Thr variant co-segregated with a noncompaction phenotype in the family with high clinical variability. Arg281Thr occurs in a conserved region of the protein, and in silico programs predict the variant destabilizes the myosin head. In many individuals in the family, other heart defects were seen along with noncompaction, including Ebstein's anomaly. Furthermore, the NHLBI ESP Exome Variant Server reports Arg281Thr was not observed in approximately 6,500 samples from individuals of European and African America backgrounds, indicating it is not a common benign variant in these populations. Based on currently available evidence, R281T is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. - |
Left ventricular noncompaction Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 03, 2015 | The p.Arg281Thr variant in MYH7 has been reported in 1 German individual with LV NC, Ebstein's anomaly and ASD, and segregated with disease in 10 affected relati ves (Budde 2007). This variant has also been identified in 1 individual with HCM (Waldmuller 2008), and was absent from large population studies. Arginine (Arg) at position 281 is highly conserved in evolution, and the change to threonine ( Thr) was predicted to be pathogenic using a computational tool clinically valida ted by our laboratory. This tool's pathogenic prediction is estimated to be corr ect 94% of the time (Jordan 2011). In summary, this variant meets our criteria t o be classified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies and absence from controls. - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 281 of the MYH7 protein (p.Arg281Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant noncompaction of the ventricular myocardium (PMID: 18159245). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181327). 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. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 30, 2023 | The p.R281T variant (also known as c.842G>C), located in coding exon 8 of the MYH7 gene, results from a G to C substitution at nucleotide position 842. The arginine at codon 281 is replaced by threonine, an amino acid with similar properties. This variant arose de novo in one individual with left ventricular noncompaction cardiomyopathy (LVNC) and segregated with LVNC with variable expression in the proband's descendants, some of whom also had Ebstein's anomaly and/or septal defects (Budde BS et al. PLoS ONE, 2007 Dec;2:e1362). This variant has been reported in other individuals with LVNC (Mazzarotto F et al. Genet Med, 2021 May;23:856-864; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at