rs199476318

Positions:

• chr15-63062588-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001018005.2(TPM1):​c.715G>A​(p.Ala239Thr) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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
• 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, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.715G>A	p.Ala239Thr	missense_variant	8/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.715G>A	p.Ala239Thr	missense_variant	8/10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3 Other:1

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 24, 2017	GENETIC TEST RESULTS This patient was diagnosed with DCM at age 5 months and underwent heart transplant at age 3 years. She had an Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae laboratory. The following 120 genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACADVL, ACTC1, ACTN2, AGL, AKAP9, ALMS1, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV3, CHRM2, CPT2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GJA5, GLA, GPD1L, HCN4, ILK, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNK3, KCNQ1, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYL4, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SLC22A5, SLMAP, SNTA1, TAZ, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL The following gene was evaluated for sequence changes only: SDHA. Results show that two variants were detected: · p.Ala239Thr (A239T; c.715G>A) in the TPM1 gene · p.Ser52Cys (S52C; c.155C>G) in the ELAC2 gene We suspect that the TPM1 variant may play a role in this patient’s heart condition, although there is not yet enough evidence to say that with certainty. p.Ala239Thr (A239T; c.715G>A) in exon 8 of the TPM1 gene (NM_001018005.1) Chromosome position: 15:63354787 G / A Based on the information reviewed below, we classify Ala239Thr as a VUS, probably disease-causing, concluding that there is not sufficient evidence at this time for its pathogenicity to warrant using it for predictive genetic testing. However, we do feel it is a good candidate to be pathogenic, and we plan to do additional testing to see if it is de novo in our patient. This variant has previously been reported in at least 2 unrelated individuals with cardiomyopathy. There is no published segregation data. It was reported by Hershberger et al. (2010) in an individual with familial dilated cardiomyopathy (PMID: 20215591). It was reported by Walsh et al. (2016) in an individual with hypertrophic cardiomyopathy who was sequenced at the Oxford Medical Genetics Laboratory (PMID: 27532257). It has not been submitted to ClinVar by a clinical testing laboratory as of December 12, 2016. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Alanine with a polar Threonine. Alanine at this location is absolutely conserved across ~100 vertebrate species for which we have data, as are multiple surrounding residues. According to the Invitae report, in silico algorithms do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A nearby missense variant (+/- 10 amino acids) has been submitted to ClinVar by multiple laboratories as solidly Pathogenic for dilated cardiomyopathy: p.Asp230Asn. The molecule is in a coiled coil structure that is formed by 2 polypeptide chains in close association with actin. The sequence exhibits a prominent seven-residues periodicity. In total the variant has not been seen in >140,000 published controls and individuals from publicly available population datasets. The variant was not observed in 246 published controls from multiple ethnicities (Hershberger et al. 2010). There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hyper -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2022	Reported in the published literature in one individual with familial DCM and one individual with HCM (Hershberger et al., 2010; Walsh et al., 2017); Reported in ClinVar in a patient who was diagnosed with DCM at age 5 months and underwent heart transplant at age 3 years (ClinVar Variant ID#31895; SCV000924969.1); 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: 27532257, 20215591) -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 16, 2018

This sequence change replaces alanine with threonine at codon 239 of the TPM1 protein (p.Ala239Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (rs199476318, ExAC no frequency). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 20215591, Invitae) and hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 31895). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic and dilated cardiomyopathy (PMID: 27532257). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;H;.;H;H;H;H;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.013	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
Polyphen		1.0, 0.91	.;.;D;D;.;.;.;D;.;.;.;.;.;P;.
Vest4		0.87
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.93

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: rs199476318; hg19: chr15-63354787;