rs397516149
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate
The NM_000257.4(MYH7):c.2470G>C(p.Val824Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V824I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.2470G>C | p.Val824Leu | missense_variant | 22/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.2470G>C | p.Val824Leu | missense_variant | 21/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.2470G>C | p.Val824Leu | missense_variant | 22/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 24, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Val824Leu v ariant in MYH7 has not been previously reported in the literature but has been i dentified in one proband with early onset HCM. The Val824Leu variant has not be en identified in large and broad European American and African American populati ons by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Va line (Val) at position 824 is highly conserved in mammals and across evolutionar ily distant species and the change to Leucine (Leu) was predicted to be pathogen ic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clinical significance. This to ol's pathogenic prediction is estimated to be correct 94% of the time (Jordan 20 11). Furthermore, two variants affecting the same codon in MYH7 (Val824Ile, Val 824Ala) have been reported in individuals with HCM (Erdmann 2003, LMM data) sugg esting that a change to this position may not be tolerated. In summary, althoug h the data support that the Val824Leu variant may be pathogenic, additional stud ies are needed to fully assess its clinical significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at