rs199476322

Positions:

chr15-63064141-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2

The NM_001018005.2(TPM1):c.850A>G(p.Ile284Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11O:1

Conservation

PhyloP100: 9.32

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Tropomyosin alpha-1 chain (size 283) in uniprot entity TPM1_HUMAN there are 61 pathogenic changes around while only 1 benign (98%) in NM_001018005.2

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). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. GenCC has associacion of the gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.

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 link	c.850A>G	p.Ile284Val	missense_variant, splice_region_variant	9/10	ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.850A>G	p.Ile284Val	missense_variant, splice_region_variant	9/10	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2024	Reported in multiple individuals with HCM, sometimes referred to as M284V due to alternate nomenclature (PMID: 25031304, 18533079, 20159828, 23674513, 27532257, 30847666); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Functional studies demonstrated this variant did not perform significantly different compared to wildtype (PMID: 30240712); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30847666, 34681814, 27532257, 20159828, 33129908, Syomin2020, 18533079, 23674513, 29447731, 34137518, 25031304, 30240712, 37652022) -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 09, 2014	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 08, 2015	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.Ile284Val (c.850A>G) in the TPM1 gene. To date this variant has been reported in two unrelated cases of HCM. Olivotto et al (2008) observed p.Ile284Val in one patient with HCM in a cohort recruited from Florence and Rome. Predmore et al (2010) reported the variant in an individual with HCM from an American clinic who had clinical genetic testing at LMM Laboratories. There is no segregation data available for the variant. This is a conservative amino acid change with a nonpolar Isoleucine replaced with a nonpolar Valine, at a position that is not conserved across species. Variants in nearby codons (p.Met281Thr, p.Thr282Ser (we classify as a variant of uncertain significance), p.Asp230Asn) have been reported in association with cardiomyopathy (Stenson P et al 2009, SCICD Cardiovascular database). This variant is in the second to last codon of the tropomyosin protein. In total the variant has not been seen in ~6650 published controls and publicly available general population samples. Olivotto et al (2008) report that the variant was absent in 150 presumably healthy Caucasian controls. The variant is not listed in dbSNP or 1000 Genomes. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of December 2012). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2023	Variant summary: TPM1 c.850A>G (p.Ile284Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250272 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.850A>G has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, or non-compaction cardiomyopathy, without evidence of causality and often reported as a VUS (e.g. Olivotto_2008, Witjas-Paalberends_2013, Helms_2014, Ho_2018, vanWaning_2018, vanLint_2019, Al-Shafai_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34137518, 25031304, 30297972, 18533079, 23674513, 30847666, 29447731). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=9) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 23, 2024	This missense variant replaces isoleucine with valine at codon 284 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not have significant effects on protein function and interaction with actin (PMID: 30240712). This variant has been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20159828, 23674513, 25031304, 27532257, 30847666), and in one individual with non-compaction cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the TPM1 protein (p.Ile284Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or TPM1-related conditions (PMID: 18533079, 23674513, 25031304, 27532257, 30847666; Invitae). This variant is also known as p.Met284Val. ClinVar contains an entry for this variant (Variation ID: 31898). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TPM1 function (PMID: 30240712). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	This missense variant replaces isoleucine with valine at codon 284 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not have significant effects on protein function and interaction with actin (PMID: 30240712). This variant has been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20159828, 23674513, 25031304, 27532257, 30847666), and in one individual with non-compaction cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The p.I284V variant (also known as c.850A>G), located in coding exon 9 of the TPM1 gene, results from an A to G substitution at nucleotide position 850. The isoleucine at codon 284 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in patients reported to have hypertrophic cardiomyopathy, though in some cases clinical details were limited, and patient reports may overlap (Olivotto I et al. Mayo Clin Proc. 2008;83:630-8; Predmore JM et al. Circulation. 2010;121:997-1004; Witjas-Paalberends ER et al. Cardiovasc Res. 2013;99:432-41; Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). Functional studies have suggested this amino acid substitution may potentially impact protein function and myofibril force generation; however, the clinical relevance of this result is unclear (Sequeira V et al. Circ Res. 2013;112:1491-505; Witjas-Paalberends ER et al. Cardiovasc Res. 2013;99:432-41). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.11

CardioboostCm

Uncertain

0.62

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.;D

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.2

M;M;.

PROVEAN

Benign

-0.38

N;.;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0070

D;.;D

Sift4G

Benign

0.23

T;.;T

Polyphen

0.0010

B;.;.

Vest4

0.77

MutPred

0.48

Gain of disorder (P = 0.2621);Gain of disorder (P = 0.2621);.;

MVP

0.86

ClinPred

0.72

GERP RS

5.8

Varity_R

0.42

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