14-23419978-TCG-TGCTTCTT
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP2
The NM_000257.4(MYH7):c.3591_3592delCGinsAAGAAGC(p.Asp1198ArgfsTer18) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000257.4 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.3591_3592delCGinsAAGAAGC | p.Asp1198ArgfsTer18 | frameshift_variant, missense_variant | Exon 27 of 40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.3591_3592delCGinsAAGAAGC | p.Asp1198ArgfsTer18 | frameshift_variant, missense_variant | Exon 26 of 39 | NP_001393933.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1198fs variant in MYH7 has not been previously reported in individuals with cardiomyop athy. This variant deletes 2 bases and inserts 7, resulting in a frameshift, whi ch is predicted to alter the protein?s amino acid sequence beginning at position 1198 and to lead to a premature termination codon 18 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. It sho uld be noted that loss of function variants in the MYH7 gene are very rare and t herefore, their phenotypic spectrum is incompletely characterized. Emerging evid ence suggests that truncating variants in MYH7 have little/no effect on their ow n but result in severe and early onset disease when a second variant is present on the other copy of the gene (LMM unpublished data). In summary, while this var iant severely impacts the protein, its clinical significance is uncertain. -
Hypertrophic cardiomyopathy Uncertain:1
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. This sequence change creates a premature translational stop signal (p.Asp1198Argfs*18) 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. This variant is present in population databases (rs755646089, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 228908). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at