rs199476322

Positions:

• chr15-63064141-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I284T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TPM1 NM_001018005.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 O:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 128 pathogenic changes around while only 5 benign (96%) in NM_001018005.2
• PP2: Missense variant where missense usually causes diseases, TPM1
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.850A>G	p.Ile284Val	missense_variant, splice_region_variant	9/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.850A>G	p.Ile284Val	missense_variant, splice_region_variant	9/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

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: 16 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726932

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: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

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:1 Uncertain:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	Reported in multiple individuals with HCM, sometimes referred to as M284V due to alternate nomenclature (Olivotto et al., 2008; Predmore et al., 2010; Witjas-Paalberends et al., 2013; Helms et al., 2014; Walsh et al., 2017; van Lint et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies demonstrated this variant did not perform significantly different compared to wildtype (Matyushenko et al., 2019); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#31898; ClinVar); This variant is associated with the following publications: (PMID: 30847666, 34681814, 27532257, 20159828, 33129908, Syomin2020, 18533079, 23674513, 25031304, 30240712) -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	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. -
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). -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 14, 2022	- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

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- -

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	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;D
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;N;N
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	D
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

Other links and lift over

dbSNP: rs199476322; hg19: chr15-63356340;