rs397516238
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_000257.4(MYH7):c.507A>T(p.Arg169Ser) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169G) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.507A>T | p.Arg169Ser | missense_variant | 6/40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.507A>T | p.Arg169Ser | missense_variant | 5/39 | NP_001393933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.507A>T | p.Arg169Ser | missense_variant | 6/40 | 1 | NM_000257.4 | ENSP00000347507.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 15, 2017 | p.Arg169Ser, c.507A>T (MYH7; NM_000257.2; Chr14g.23901711T>A; GRCh37): The p.Arg 169Ser variant in MYH7 has not been previously reported in individuals with HCM and was absent from large population studies. Arginine (Arg) at position 169 is highly conserved in mammals and across evolutionarily distant species and the ch ange to Serine (Ser) was predicted to be pathogenic using a computational tool c linically validated by our laboratory. This tool's pathogenic prediction is esti mated to be correct 94% of the time (Jordan 2011). Of note, this variant lies in the head region of the protein. Missense variants in this region have been repo rted and statistically indicated to be more likely to cause disease (Walsh 2016) . In addition, two other amino acid substitutions involving this codon, p.Arg169 Gly and p.Arg169Lys, have also been identified in affected individuals (Maron 20 09, LMM data). In summary, although additional studies are required to fully est ablish its clinical significance, the p.Arg169Ser variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at