rs397516369

Positions:

chr15-63057081-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The ENST00000403994.9(TPM1):c.337C>G(p.Leu113Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPM1
ENST00000403994.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.13

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_pathogenic. Variant got 8 ACMG points.

PM1

In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 129 pathogenic changes around while only 5 benign (96%) in ENST00000403994.9

PM2

Very rare variant in population databases, with high coverage;

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, 0.904

PP5

Variant 15-63057081-C-G is Pathogenic according to our data. Variant chr15-63057081-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43414.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr15-63057081-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.337C>G	p.Leu113Val	missense_variant	3/10	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.337C>G	p.Leu113Val	missense_variant	3/10	1	NM_001018005.2	ENSP00000385107	A1	P09493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Left ventricular noncompaction 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2019

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2016

The L113V likely pathogenic variant in the TPM1 gene has been previously reported in at least two unrelated families in association with DCM (Pugh et al., 2014; Cuenca et al., 2016). The L113V variant was first reported in a six-month-old Caucasian female with a clinical diagnosis of DCM, who had no history of skeletal myopathy or family history of DCM (Pugh et al., 2014), although further segregation data was not available. This variant was subsequently reported in a Spanish individual with DCM who required a heart transplant at 25 years of age, and segregation studies revealed L113V was also present in three other relatives with DCM, one relative with borderline DCM and one relative with sudden cardiac death at the age of 30 years (Cuenca et al., 2016). Furthermore, the L113V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although L113V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this variant occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is likely pathogenic. -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2013

The Leu113Val variant in TPM1 has not been reported in the literature, but has p reviously been identified by our laboratory in 1 Caucasian infant with DCM. This variant has not been identified in large and broad European American and Africa n American populations by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS), which increases the likelihood that it is pathogenic. However, we cannot exclude that it may be common in other populations. Leucine (Leu) at a mino acid position 113 is highly conserved across mammals and evolutionarily dis tant species and the change to valine (Val) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathog enic prediction is estimated to be correct 94% of the time (Jordan 2011). In sum mary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2018

The p.L113V variant (also known as c.337C>G), located in coding exon 3 of the TPM1 gene, results from a C to G substitution at nucleotide position 337. The leucine at codon 113 is replaced by valine, an amino acid with highly similar properties. This variant was detected in two families with left ventricular non-compaction (LVNC), both families demonstrated segregation in multiple relatives; some affected individuals in the second family also had Ebstein anomaly and/or mitral valve insufficiency (Cuenca S et al. J. Heart Lung Transplant., 2016 May;35:625-35; Nijak A et al. Eur J Med Genet, 2018 Jan;61:8-10). This variant has also been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2022

This missense change has been observed in individual(s) with dilated cardiomyopathy or left ventricular noncompaction (PMID: 26899768, 29024827). It has also been observed to segregate with disease in related individuals. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43414). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 113 of the TPM1 protein (p.Leu113Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

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

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

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

0.87

PROVEAN

Uncertain

-2.5

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

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.040

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

Polyphen

0.83, 0.58, 0.85, 0.99

.;.;P;P;.;.;.;P;.;.;.;.;.;D;.

Vest4

0.76

MutPred

0.65

.;.;.;Gain of methylation at K154 (P = 0.0335);.;.;.;.;.;.;.;.;.;.;.;

MVP

0.93

MPC

2.5

ClinPred

1.0

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.99

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