rs397516382

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_001018005.2(TPM1):c.64G>A(p.Ala22Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,694 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 7.82

Publications

4 publications found

Variant links:

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 links:

TPM1-AS (HGNC:53635): (TPM1 antisense RNA)

TPM1-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_001018005.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

PP5

Variant 15-63042893-G-A is Pathogenic according to our data. Variant chr15-63042893-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43432.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.64G>A	p.Ala22Thr	missense_variant	Exon 1 of 10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.64G>A	p.Ala22Thr	missense_variant	Exon 1 of 10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000812

AC:

AN:

246308

AF XY:

0.00000748

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726422

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111232

Other (OTH)

AF:

0.00

AC:

AN:

60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74488

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000481

AC:

AN:

41592

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jul 16, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely pathogenic

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. p.Ala22Thr (c.64 G>A) in TPM1. Given case data and absence in ancestry- matched controls we consider this variant likely disease causing. The variant has been seen in at least 4 unrelated cases of HCM (not including this patient's family). There is weak segregation data in one family. Otsuko et al (2011) observed the variant in one patient from their cohort of 112 unrelated Japanese patients with HCM. The variant segregated with disease in two affected first degree relatives. The variant is listed in ClinVar, with data submitted by LMM (SCV000060003). They note that they have observed the variant in two Black patients with HCM. They classify it as a variant of uncertain significance and last reviewed it in December 2012. We have seen the variant in one other patient in our center, a patient with HCM of mixed ancestry (Korean, Black, Native American, Mongolian). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The alanine at codon 22 is conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with disease at nearby codons: p.Arg21His (Fokstuen et al 2011), p.Glu23Gln (Hershberger et al 2010), p.Asp28Asn (Bos et al 2013). In total the variant has not been seen in ~7100 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 22 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 16th, 2014). The ClinVar entry from LMM notes that coverage was insufficient in ESP to assess this variant’s presence. The variant is listed in dbSNP, pointing to the LMM data (as of June 9th, 2014). The variant was not observed in the following laboratory and published control samples: 200 Japanese individuals who were presumed healthy (Otsuko et al 2011). -

Jul 15, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with HCM referred for genetic testing at GeneDx and in published literature and segregated with disease in two individuals from one family (PMID: 22112859, 25524337, 25611685, 37652022); 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; This variant is associated with the following publications: (PMID: 25524337, 27532257, 25611685, 22112859, 37652022) -

Hypertrophic cardiomyopathy 3

Pathogenic:1

Mar 11, 2024

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.82 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.60 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TPM1 related disorder (ClinVar ID: VCV000043432 /PMID: 22112859 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Hypertrophic cardiomyopathy

Pathogenic:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 22 of the TPM1 protein (p.Ala22Thr). This variant is present in population databases (rs397516382, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22112859, 25524337, 27532257, 37652022; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43432). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Aug 16, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A22T variant (also known as c.64G>A), located in coding exon 1 of the TPM1 gene, results from a G to A substitution at nucleotide position 64. The alanine at codon 22 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in one relative (Otsuka H et al. Circ. J. 2012;76:453-61; Coppini R et al. J. Am. Coll. Cardiol. 2014;64:2589-600; Alfares AA et al. Genet. Med. 2015;17:880-8; Ambry internal data). 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. -

not specified

Uncertain:1

Mar 06, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala22Thr variant in TPM1 has been reported in 4 individuals with clinical features of HCM and segregated with disease in one affected relative (Otsuka 2012, Walsh 2016, Schymanski 2017). This variant has also been reported in ClinVar (Variation ID 4 3432) and has been identified in 1/14848 African chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516382). A lanine (Ala) at position 22 is highly conserved in mammals and across evolutiona rily distant species, and the change to threonine (Thr) was predicted to be path ogenic using a computational tool clinically validated by our laboratory. This t ool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2 011). In summary, while there is some suspicion for a pathogenic role, the clini cal significance of the p.Ala22Thr variant is uncertain. ACMG/AMP Criteria appli ed: PM2; PP3; PS4_Supporting. -

Cardiomyopathy

Uncertain:1

Feb 13, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

.;.;D;.;D;D;.;.;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;H;.;.;H;.;H;H;H;H;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.1

N;N;.;D;N;N;N;N;N;N;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;.;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0, 0.99

.;.;.;.;D;D;.;.;.;D;.

Vest4

0.85

MutPred

0.34

Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);

MVP

0.94

MPC

2.4

ClinPred

1.0

GERP RS

4.6

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.76

gMVP

0.95

Mutation Taster

=1/99

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over