rs730881151

Positions:

chr15-63042891-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1PM5PP2PP3PP5BS2

The ENST00000403994.9(TPM1):c.62G>T(p.Arg21Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,552 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. R21G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TPM1
ENST00000403994.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:9

Conservation

PhyloP100: 7.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000403994.9

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-63042890-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

PP5

Variant 15-63042891-G-T is Pathogenic according to our data. Variant chr15-63042891-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181678.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=9}.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.62G>T	p.Arg21Leu	missense_variant	1/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 linkuse as main transcript	c.62G>T	p.Arg21Leu	missense_variant	1/10	1	NM_001018005.2	ENSP00000385107	A1	P09493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246812

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460552

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000185

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2024	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Nov 22, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 24, 2024	This missense variant replaces arginine with leucine at codon 21 in the actin binding region of the TPM1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 30 families affected with hypertrophic cardiomyopathy (PMID: 33642254). Overall, 39 heterozygous affected individuals (age range 11-73 years) and 5 homozygous individuals (age range 40-71 years) were observed in this study with highly variable age of onset, as well as 22 heterozygous unaffected individual (age range 9-80 years). This variant has been shown to segregate with disease in 8 families (11 informative segregations) (PMID: 33642254). This variant has also been reported in 4 other unrelated heterozygous individuals affected with hypertrophic cardiomyopathy (PMID: 28138913, 28771489, 28797094, 33642254, 37498360), one of whom carried a pathogenic variant in the MYBPC3 gene (PMID: 28771489). This variant has also been reported in an individual affected with sudden death (PMID: 33642254). This variant has been identified in 5/246812 chromosomes (5/34311of Latino) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 21 of the TPM1 protein (p.Arg21Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 28138913, 33642254; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181678). 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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 25, 2024	Identified in an individual who suffered sudden death at rest and harbored additional cardiogenetic variants (PMID: 33919104); 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: 29105867, 28138913, 28797094, 34426522, 33642254, 31983221, 30681346, 37498360, 37652022, 33919104, 28771489, 33495597, 38874371) -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 03, 2021	- -

Hypertrophic cardiomyopathy 3

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene have been associated with late-onset disease or incomplete penetrance (PMIDs: 33642254; 32882290, 32731933). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg21His) variant has been reported in one HCM individual, while the p.(Arg21Cys) variant has been reported in two unrelated HCM individuals, although there is limited information provided (PMIDs: 16005017, 21239446). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified multiple times as VUS and has been identified in multiple individuals with HCM and other cardiac-related phenotypes, a number of whom also harboured a likely pathogenic or pathogenic variant in MYBPC3 or VUS in other cardiac genes (personal communication from ClinVar submitters; PMIDs: 28771489, 33919104, 33642254, 33495597). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiomyopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 13, 2023	This missense variant replaces arginine with leucine at codon 21 in the actin binding region of the TPM1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 30 families affected with hypertrophic cardiomyopathy (PMID: 33642254). Overall, 39 heterozygous affected individuals (age range 11-73 years) and 5 homozygous individuals (age range 40-71 years) were observed in this study with highly variable age of onset, as well as 22 heterozygous unaffected individual (age range 9-80 years). This variant has been shown to segregate with disease in 8 families (11 informative segregations) (PMID: 33642254). This variant has also been reported in 4 other unrelated heterozygous individuals affected with hypertrophic cardiomyopathy (PMID: 28138913, 28771489, 28797094, 33642254, 37498360), one of whom carried a pathogenic variant in the MYBPC3 gene (PMID: 28771489). This variant has also been reported in an individual affected with sudden death (PMID: 33642254). This variant has been identified in 5/246812 chromosomes (5/34311of Latino) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 22, 2022	- -

Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 22, 2023

The c.62G>T variant in TPM1 has previously been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and sudden death in homozygous, heterozygous, and also found to co-occur with additional gene variants [PMID: 28138913, 28797094, 33919104, 33642254]. Additionally, this variant was reported to be absent in controls, was found to segregate with disease, and associated with late-onset, incomplete penetrance, and milder clinical course [PMID: 33642254]. This variant has been deposited in ClinVar [ClinVar ID: 181678] as Variant of Uncertain Significance/Likely Pathogenic. The c.62G>T variant is observed in 22 alleles (~0.004% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.62G>T variant in TPM1 is located in exon 1 of this 10-exon gene and predicted to replace an evolutionarily conserved arginine amino acid with leucine at position 21 in the N-terminal region of the encoded protein which is reported to be crucial for binding of TPM1 with actin protein [PMID:26873245, 11964245, 30240712, 33642254]. In silico predictions are in favor of damaging effect for p.(Arg21Leu) [(CADD v1.6 = 24.3, REVEL = 0.773)]; however, there are no functional studies to support or refute these predictions. Another missense substitution affecting the same protein residue p.(Arg21His) has previously been identified in an individual with hypertrophic cardiomyopathy and shown to be functionally damaging [PMID: 21239446, 29105867]. Based on available evidence this c.62G>T p.(Arg21Leu) variant identified in TPM1 is classified as Likely Pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 23, 2024

Variant summary: TPM1 c.62G>T (p.Arg21Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246812 control chromosomes. c.62G>T has been reported in the literature in the heterozygous or homozygous (rarely) state in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Lamounier Junior_2022) and has been suggested to be a founder variant in Portugual and Spain. These data indicate that the variant is very likely to be associated with disease, and the authors of that study found a primarily late-onset, moderate penetrance presentation among the clinically evaluated families (Lamounier Junior_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33642254). ClinVar contains an entry for this variant (Variation ID: 181678). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 06, 2021

ACMG classification criteria: PM2, PP3 -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The p.R21L variant (also known as c.62G>T), located in coding exon 1 of the TPM1 gene, results from a G to T substitution at nucleotide position 62. The arginine at codon 21 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals from hypertrophic cardiomyopathy (HCM) and sudden death cohots; however, in some cases clinical detail was limited or co-occurring variants were detected (Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Mademont-Soler I et al. PLoS One. 2017 Aug;12(8):e0181465; Mendes de Almeida R et al. PLoS ONE, 2017 Aug;12:e0182946; Iglesias M et al. J Clin Med. 2021 Apr;10(9)). In one study, this variant was detected in several HCM cases from Spain and Portugal, was reported to segregate with disease, and was considered associated with late-onset, incomplete penetrance, and milder clinical course; however, details were not available and several cases had co-occurring variants (Lamounier Junior A. Rev Esp Cardiol (Engl Ed). 2021 Feb; [Online ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

CardioboostCm

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

.;.;T;.;D;T;.;.;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.75

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;.;.;M;.;M;M;M;M;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.054

T;T;D;D;T;T;T;T;T;.;.

Polyphen

0.0020, 0.99, 0.018

.;.;.;.;B;D;.;.;.;B;.

Vest4

0.90

MutPred

0.34

Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);

MVP

0.99

MPC

2.1

ClinPred

0.97

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.91

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over