rs199476320
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3
The NM_001018005.2(TPM1):āc.830C>Gā(p.Ala277Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,234 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A277T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.830C>G | p.Ala277Gly | missense_variant | 9/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.830C>G | p.Ala277Gly | missense_variant | 9/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
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 | Dec 31, 2018 | proposed classification - variant undergoing re-assessment, contact laboratory - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2012 | The Ala277Gly variant in the TPM1 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. However, Ala277Val has been reported in a patient with severe idiopathic DCM who required a heart transplant at age 13, and Ala277Val was absent from 413 control individuals of various ethnic backgrounds (Hershberger R et al., 2010; Rampersaud E et al., 2011). However, this individual also harbored a mutation in the TNNT2 gene (Hershberger R et al., 2010; Rampersaud E et al., 2011). Ala277Gly is a conservative amino acid substitution of one non-polar amino acid for another at a position that is conserved across species. A mutation in a nearby codon (Met281Thr) has been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ala277Gly was not observed in over 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common variant in these populations. In summary, with the clinical and molecular information available at this time, we cannot determine whether Ala277Gly in the TPM1 gene is a disease-causing mutation or a benign variant. The variant is found in DCM panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at