rs397516375

Positions:

• chr15-63060909-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The ENST00000403994.9(TPM1):​c.533G>A​(p.Arg178His) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R178R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 ENST00000403994.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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, 0.899
• PP5: Variant 15-63060909-G-A is Pathogenic according to our data. Variant chr15-63060909-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43423.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.533G>A	p.Arg178His	missense_variant	5/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.533G>A	p.Arg178His	missense_variant	5/10	1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1Y Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Feb 18, 2021

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2024

Reported as de novo without confirmed parentage or of unknown inheritance in individuals with cardiomegaly, heart failure, left ventricular non-compaction, restrictive cardiomyopathy, and/or dilated cardiomyopathy tested at GeneDx and in published literature (PMID: 29644095, 30188508, 32600061, 34036930, 36252119, 34645491); 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; Functional studies using human-induced pluripotent stem cells from a patient harboring the p.(R178H) variant showed impaired tropomyosin 1 localization, sarcomere structure, and calcium handling (PMID: 30188508); This variant is associated with the following publications: (PMID: 32600061, 33888711, 34036930, 31019026, 29644095, 30188508, 36252119, 34645491, 37952715) -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 03, 2023

The TPM1 c.533G>A variant is classified as Pathogenic (PS2, PS3, PS4_Moderate, PM2, PP3) The TPM1 c.533G>A variant is a single nucleotide change in exon 5/10 of the TPM1 gene, which is predicted to change the amino acid arginine at position 178 in the protein, to histidine. This variant has been identified as a de novo variant in this patient (PS2). The variant has been reported in greater than 6 probands with a clinical presentation of infant/childhood-onset left ventricular non-compaction/dilated cardiomyopathy/cardiomyopathy (PMID#30188508,29644095,36252119, 34036930) (PS4_Moderate) and is absent from population databases (PM2). Well-established functional studies of this variant in human-induced pluripotent stem cells (cardiomyocyte induced), show a deleterious effect with mis-localisation of tropomyosin 1 resulting in the disruption of the sarcomere and impaired calcium handling (PMID#30188508) (PS3). The variant has been reported in dbSNP (rs397516375), is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 43423) and is reported as disease causing in HGMD (CM186474). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2022

The p.R178H variant (also known as c.533G>A), located in coding exon 5 of the TPM1 gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in three cases in the literature with left ventricular noncompaction or dilated cardiomyopathy presenting with or progressing to heart failure within the first year of life (Takasaki A et al. Pediatr Res, 2018 11;84:733-742; Farnaes L et al. NPJ Genom Med, 2018 Apr;3:10; Mehaney DA et al. Cardiol Young, 2022 Feb;32:295-300). In addition, this variant was confirmed de novo in a neonate with ascites, diffuse edema, and cardiomegaly with multi-chamber enlargement (Genomic Medicine Lab, University of California San Francisco pers. comm.). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)), and is 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg178His v ariant in TPM1 has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large and broa d European American and African American populations screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) but it remains possible t hat this variant is common in other populations. Arginine (Arg) at position 178 is conserved in evolution and the change to Histidine (His) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. T his tool's pathogenic prediction is estimated to be correct 94% of the time (Jor dan 2011). Although this data supports that the Arg178His variant may be pathoge nic, additional studies are needed to fully assess its clinical significance. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2022

ClinVar contains an entry for this variant (Variation ID: 43423). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 29644095, 30188508, 34036930; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the TPM1 protein (p.Arg178His). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;T;T;T;D;D;D;T;D;T;T;D;T;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;M;.;M;M;M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
Sift4G	Benign	0.064	T;T;D;D;D;D;D;.;.;D;D;.;D;D;D;D
Polyphen		0.96, 0.92, 0.72, 0.84	.;.;D;P;.;.;.;P;.;.;.;.;.;P;.;.
Vest4		0.72
MutPred		0.68		.;.;.;Gain of helix (P = 0.0861);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		2.7
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.89

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: rs397516375; hg19: chr15-63353108;