rs199476307
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_001018005.2(TPM1):c.209A>C(p.Lys70Thr) 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. K70R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.209A>C | p.Lys70Thr | missense_variant | 2/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.209A>C | p.Lys70Thr | missense_variant | 2/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2022 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 70 of the TPM1 protein (p.Lys70Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mild hypertrophic cardiomyopathy (PMID: 8774330). ClinVar contains an entry for this variant (Variation ID: 31878). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TPM1 function (PMID: 12900417, 15479242, 25241052). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2019 | The c.209A>C (p.K70T) alteration is located in exon 2 (coding exon 2) of the TPM1 gene. This alteration results from a A to C substitution at nucleotide position 209, causing the lysine (K) at amino acid position 70 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at