rs727503517

Positions:

• chr15-63059577-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001018005.2(TPM1):​c.389T>C​(p.Ile130Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. I130V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63059576-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370041.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.899
• PP5: Variant 15-63059577-T-C is Pathogenic according to our data. Variant chr15-63059577-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165566.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.389T>C	p.Ile130Thr	missense_variant	4/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.389T>C	p.Ile130Thr	missense_variant	4/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces isoleucine with threonine at codon 130 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 reported in an individual affected with congenital cardiac anomalies and cardiomyopathy (PMID: 30513141). It has also been reported in individuals affected with dilated cardiomyopathy (ClinVar variation ID: 165566). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 130 of the TPM1 protein (p.Ile130Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of dilated cardiomyopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 165566). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 24, 2017	TPM1, Exon 4, c.389T>C (p.Ile130Thr), heterozygous, Uncertain Significance We have seen this variant in one patient in our center with DCM and a family history of DCM. Given it is rare but with only minimal case data and no segregation data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated case of DCM (not including this patient's family). There is so segregation data. LMM has an entry in ClinVar, as a variant of uncertain significance and they note they have seen it in one patient with DCM. There is no variation at codon 130 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >30x. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	Reported in a family in which the proband and father expressed phenotypes consistent with Timothy syndrome, and both harbored the c.3717+1_3717+2insA variant in the CACNA1C gene, which was felt to be causative. The proband additionally harbored the I130T variant in the TPM1 gene, which was not observed in the affected father, and the mother did not undergo testing (Bozarth et al., 2018).; Not observed 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: 28359939, 30513141) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2024

The p.I130T variant (also known as c.389T>C), located in coding exon 4 of the TPM1 gene, results from a T to C substitution at nucleotide position 389. The isoleucine at codon 130 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in subjects with dilated cardiomyopathy (DCM) and has been shown to segregate with disease (Perret C et al. Clin Genet, 2024 Feb;105:185-189; Ambry internal data; external communication). This alteration has also been reported in a subject with features of Timothy syndrome, who had variants in other cardiac-related genes (Bozarth X et al. Am J Med Genet A, 2018 Dec;176:2733-2739). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 14, 2023

This missense variant replaces isoleucine with threonine at codon 130 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 reported in an individual affected with congenital cardiac anomalies and cardiomyopathy (PMID: 30513141). It has also been reported in individuals affected with dilated cardiomyopathy (ClinVar variation ID: 165566). 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

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 20, 2022

The p.Ile130Thr variant in TPM1 has been identified in 1 individual with dilated cardiomyopathy (DCM) and 1 family member with left ventricle enlargement and mild decreased systolic function (LMM Data). It has also been identified in 1 individual with cardiac anomalies and cardiomyopathy who carried a second variant in a gene that may potentially explain their disease (Bozarth 2018, PMID: 30513141). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 165566) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;.
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D;D;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;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.039	D;D;D;D;D;D;T;.;.;D;T;.;T;D;D;T;.
Polyphen		0.50, 1.0, 0.86, 0.20	.;.;P;D;.;.;.;P;.;.;.;.;.;B;.;.;.
Vest4		0.88
MutPred		0.66		.;.;.;Gain of phosphorylation at I172 (P = 0.0152);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727503517; hg19: chr15-63351776;