rs199476317
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong
The NM_001018005.2(TPM1):c.688G>A(p.Asp230Asn) variant causes a 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
TPM1
NM_001018005.2 missense
NM_001018005.2 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 9.88
Genes affected
TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001018005.2
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TPM1
PP5
?
Variant 15-63062263-G-A is Pathogenic according to our data. Variant chr15-63062263-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63062263-G-A is described in Lovd as [Pathogenic]. Variant chr15-63062263-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.688G>A | p.Asp230Asn | missense_variant | 7/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.688G>A | p.Asp230Asn | missense_variant | 7/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2022 | Reported in association with dilated cardiomyopathy (Lakdawala et al., 2010; Pugh et al., 2014; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant significantly impairs sarcomere function compared to wild-type TPM1 protein (Lakdawala et al., 2010; Memo et al., 2013); This variant is associated with the following publications: (PMID: 23539503, 25548289, 23836688, 25202278, 25241052, 25525159, 21310275, 28166811, 23281406, 25179549, 21483645, 24503780, 27872154, 28600229, 31216405, 31983221, 20117437, 27532257, 34935411) - |
Pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Nov 07, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp230Asn (c.688 G>A) in TPM1 The variant has been seen in at least 2 unrelated cases of familial DCM with strong segregation data (not including our patient's family). Lakdawala et al (2010) observed the variant in two Caucasian families with DCM. Ten affected members of one family and 6 affected members of there other family carried the variant. The authors report that 21 of 25 unaffected adult family members did not have the variant. The combined LOD score was 5.22. There was marked intrafamilial variability with some family members diagnosed in the first year of life and others diagnosed in mid-adulthood. The same group later reported on early phenotypes in DCM including individuals with p.Asp230Asn (Lakdawala et al 2012). Presumably these were the same families as their prior report. This is a non-conservative amino acid substitution. The aspartate at codon 230 is conserved across species. PolyPhen predicts the variant to be possibly damaging. Lakdawala et al (2010) assessed the impact of the variant using an in vitro reconstituted sarcomere complex. They found inhibited sarcomere function with reduced calcium sensitivity, maximum activation and calcium affinity. A nearby variant has been reported in association with DCM, p.Ala239Thr (Stenson et al 2009). In total the variants has not been seen in at least 7000 published controls and publicly available general population samples. Lakdawala et al (2010) did not observe the variant in >500 Caucasian individuals. There is no variation at codon 230 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 28th, 2012). The variant is not listed in 1000 genomes (as of October 28th, 2012). It is listed in dbSNP, pointing to an online database for TPM1 variants that cites Lakdawala et al (2010). - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 11, 2016 | - - |
Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2018 | - - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 13, 2015 | The p.Asp230Asn variant in TPM1 has been identified in 2 Caucasian individuals w ith DCM and segregated with disease in 14 affected relatives (Lakdawala 2010, LM M unpublished data). This variant was absent from large population studies. In a ddition, in vitro studies supported that this variant impacts contractility (Lak dawala 2010). In summary, the p.Asp230Asn variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based on segregation and abs ence in controls. - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 230 of the TPM1 protein (p.Asp230Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20117437, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31884). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 23539503, 25242052, 25548289, 28600229, 28603979). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M;.;M;M;M;M;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;.;.;D;T;.;D;D;D;T
Sift4G
Benign
T;T;T;T;T;T;T;.;.;T;T;.;T;D;T;D
Polyphen
0.91, 0.28, 0.25, 0.99
.;.;P;B;.;.;.;B;.;.;.;.;.;D;.;.
Vest4
MutPred
0.60
.;.;.;Gain of MoRF binding (P = 0.0548);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
MPC
2.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at