rs397516387

Variant names:

• chr15-63062598-C-T
• rs397516387
• NM_001018005.2:c.725C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001018005.2(TPM1):​c.725C>T​(p.Ala242Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A242T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 7.91
• Publications: 7 publications found

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]

TPM1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• dilated cardiomyopathy 1Y

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63062597-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4085578.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 15-63062598-C-T is Pathogenic according to our data. Variant chr15-63062598-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43437.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.725C>T	p.Ala242Val	missense_variant	Exon 8 of 10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.725C>T	p.Ala242Val	missense_variant	Exon 8 of 10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:1 Uncertain:1

Jun 01, 2023

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala242Val variant in TPM1 has been reported in at least 5 individuals with dilated cardiomyopathy (DCM; Walsh 2017 PMID: 27532257, Van Lint 2019 PMID: 30847666, Khan 2022 PMID: 34935411, LMM data), in at least 2 individuals with left ventricular non-compaction (LVNC; Tian 2015 PMID: 24691700, Li 2018 PMID: 30371277, Miszalski-Jamka 2018 PMID: 28798025) and in 1 individual with left ventricular dysfunction and unspecified cardiomyopathy in whom the variant occurred de novo (Invitae Personal Communication 2023). In one of individuals with DCM, this variant was also identified in an affected relative with DCM (LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43437) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PS2_Supporting, PP3. -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the TPM1 protein (p.Ala242Val). This variant is present in population databases (rs397516387, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 24691700, 27532257, 30847666, 34935411; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43437). 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. For these reasons, this variant has been classified as Pathogenic. -

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with valine at codon 242 in the alternate splicing region of the TPM1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 30847666, 34935411, 36178741); in one instance, this variant was reported to occur de novo (PMID: 36178741). This variant has also been reported in individuals affected with left ventricular noncompaction cardiomyopathy (PMID: 24691700, 28798025, 30371277, 37342443). One of these individuals also carried a truncating variant in the TTN gene (PMID: 28798025). It has been shown that this variant segregates with disease in five affected individuals from one family affected with left ventricular noncompaction cardiomyopathy (PMID: 37342443). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been shown to be associated with dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy (ClinVar variation ID: 43437), additional studies are necessary to determine the role of this variant in autosomal dominant hypertrophic cardiomyopathy. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dilated cardiomyopathy 1Y Pathogenic:1

Jul 17, 2020

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene substitutes a well conserved Alanine for Valine at amino acid 242/285 (exon 8/10). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (Provean; score:-3.3) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:43437), and has been identified in several individuals in the literature with left ventricular non-compaction [PMID:24691700; PMID:30371277; PMID:28798025] and dilated cardiomyopathy [PMID:27532257; PMID:24503780; PMID:30847666]. Given its absence in population databases, in silico prediction of damaging effect to protein function, and its observation in several affected individuals in the literature, the heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene is reported as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Aug 25, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A242V variant (also known as c.725C>T), located in coding exon 8 of the TPM1 gene, results from a C to T substitution at nucleotide position 725. The alanine at codon 242 is replaced by valine, an amino acid with similar properties. This variant has been detected in several unrelated individuals with dilated cardiomyopathy (DCM) and/or left ventricular noncompaction cardiomyopathy (LVNC), including a reported de novo occurrence and reported segregation with disease in a family (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Tian T et al. Heart Vessels, 2015 Mar;30:258-64; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854; van der Meulen MH et al. Circ Genom Precis Med, 2022 Oct;15:e002981; Meshkov AN et al. Front Cardiovasc Med, 2023 May;10:1205787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;D;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;H;.;H;H;H;H;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
Polyphen		1.0, 0.98, 1.0, 1.0	.;.;D;D;.;.;.;D;.;.;.;.;.;D;.
Vest4		0.94
MutPred		0.72		.;.;.;Loss of phosphorylation at T279 (P = 0.1593);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.93
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.97
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516387; hg19: chr15-63354797; COSMIC: COSV104570190; COSMIC: COSV104570190;