NM_000257.4:c.2377C>T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_000257.4(MYH7):c.2377C>T(p.Arg793*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,892 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000257.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727248
GnomAD4 genome
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
This variant changes 1 nucleotide in exon 21 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute myocarditis (PMID: 34368507). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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. -
This variant changes 1 nucleotide in exon 21 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute myocarditis (PMID: 34368507). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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
Variant summary: MYH7 c.2377C>T (p.Arg793X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay in a gene where molecular mechanism of disease is gain of function. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2377C>T has been reported in the literature in an individual affected with acute myocarditis and the authors classifed the variant as VUS (example:Kontorovich_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34368507). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease -
Hypertrophic cardiomyopathy Uncertain:1
This sequence change creates a premature translational stop signal (p.Arg793*) in the MYH7 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. 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. ClinVar contains an entry for this variant (Variation ID: 574743). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). -
Cardiovascular phenotype Uncertain:1
The p.R793* variant (also known as c.2377C>T), located in coding exon 19 of the MYH7 gene, results from a C to T substitution at nucleotide position 2377. This changes the amino acid from an arginine to a stop codon within coding exon 19. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MYH7 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
MYH7-related disorder Uncertain:1
The MYH7 c.2377C>T variant is predicted to result in premature protein termination (p.Arg793*). This variant has been reported in an individual with acute myocarditis (Kontorovich et al. 2021. PubMed ID: 34368507). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
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