rs727504354

Variant names:

• chr15-63062635-T-A
• rs727504354
• NM_001018005.2:c.762T>A

Your query was ambiguous. Multiple possible variants found:

• chr15-63062635-T-A
• chr15-63062635-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001018005.2(TPM1):​c.762T>A​(p.Asp254Glu) 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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D254G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.24
• Publications: 2 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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.762T>A	p.Asp254Glu	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.762T>A	p.Asp254Glu	missense_variant	Exon 8 of 10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 24, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. The genetic test results were re-reviewed January 7th, 2014 and again on July 7th, 2015. There is new case and control data. p.Asp254Glu (c.762 T>A) in the TPM1 gene. We have seen this in a father and son who both have restrictive cardiomyopathy. Based on the moderate case data and absence in controls, we consider it a variant of uncertain significance, probably disease causing. The variant has been seen in at least 2 unrelated cases of HCM (not including this patent's case). The testing lab shared that they have seen it in one other family. Specifically, an individual diagnosed with HCM <20yo, with a family history of HCM and sudden death. Another testing lab shared that they have seen the variant in a 40yo Black female with HCM and a family history of sudden death. In silico analysis with PolyPhen 2 predicts the variant to be probably damaging. No other variants have been reported in association with disease at codon 254 or nearby codons. This is a non-conservative amino acid change at a highly conserved position. In total this variant has not been seen in ~70,471 laboratory controls and publicly available general population samples. There is no variation at codon 254 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6200 Caucasian and African American individuals (as of January 7th, 2014). GeneDx did not observe the variant in 271 normal control individuals of different ethnic backgrounds. There is no variation at codon 254 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 7th, 2015).

Hypertrophic cardiomyopathy Uncertain:1

Nov 27, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 235068). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 254 of the TPM1 protein (p.Asp254Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid.

Cardiovascular phenotype Uncertain:1

Aug 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D254E variant (also known as c.762T>A), located in coding exon 8 of the TPM1 gene, results from a T to A substitution at nucleotide position 762. The aspartic acid at codon 254 is replaced by glutamic acid, an amino acid with highly similar properties. Other variant(s) resulting in the same amino acid change (c.762T>G) have been identified in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). 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 available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;.;H;H;H;H;.;.;.;.;.;.;.
PhyloP100		2.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
Sift4G	Benign	0.15	T;T;T;T;T;T;T;.;.;T;T;.;T;T;T
Vest4		0.84
ClinPred		1.0	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.88
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs727504354; hg19: chr15-63354834;