chr14-23415174-G-C
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_000257.4(MYH7):c.5380C>G(p.Gln1794Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1794K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- dilated cardiomyopathy 1SInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- MYH7-related skeletal myopathyInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- myopathy, myosin storage, autosomal recessiveInheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- myopathy, myosin storage, autosomal dominantInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- congenital myopathy 7A, myosin storage, autosomal dominantInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Ebstein anomalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hyaline body myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- left ventricular noncompactionInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- congenital heart diseaseInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5380C>G | p.Gln1794Glu | missense_variant | Exon 37 of 40 | 1 | NM_000257.4 | ENSP00000347507.3 | ||
MYH7 | ENST00000713768.1 | c.5380C>G | p.Gln1794Glu | missense_variant | Exon 37 of 41 | ENSP00000519070.1 | ||||
MYH7 | ENST00000713769.1 | c.5380C>G | p.Gln1794Glu | missense_variant | Exon 36 of 39 | ENSP00000519071.1 | ||||
ENSG00000258444 | ENST00000557368.1 | n.-165G>C | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardiomyopathy Pathogenic:1
- -
not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28606303, 20474083, 22464770, 27532257, 24503780, 37652022) -
Hypertrophic cardiomyopathy Uncertain:1
In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 22464770). ClinVar contains an entry for this variant (Variation ID: 43067). This variant is not present in population databases (rs397516247, ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 1794 of the MYH7 protein (p.Gln1794Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at