rs199476315

Positions:

• chr15-63061723-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001018005.2(TPM1):​c.574G>A​(p.Glu192Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,812 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a coiled_coil_region (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, 0.915
• PP5: Variant 15-63061723-G-A is Pathogenic according to our data. Variant chr15-63061723-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63061723-G-A is described in Lovd as [Pathogenic]. Variant chr15-63061723-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.574G>A	p.Glu192Lys	missense_variant	6/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.574G>A	p.Glu192Lys	missense_variant	6/10	1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000157 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	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, 12858563, 12860912, 25241052, 23700264, 21415410, 24510615, 20031602, 21551322, 26960954, 27639548, 21310275, 16365313, 25524337, 18409188, 23771913, 27376658, 25611685, 23396983, 24033266, 31006259, 34319370, 28193612, 35176663, 33297573, 34540771, 28615295) -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 05, 2016	p.Glu192Lys (c.574G>A) in the TPM1 gene. Seen in our center in an adult with HCM with a family history of HCM and sudden death. We re-reviewed the results August 4th, 2016. We had initially classified this as a VUS. Given the strong case data and absence in controls we now consider the variant likely pathogenic and we do feel it is appropriate for assessing risk in healthy relatives (predictive genetic testing). Seen in at least 18 presumably unrelated cases of HCM (7 published, 11 unpublished) and one case of LVNC. It has segregated with disease in at least three affected relatives. Deva et al. (2013) reported this variant in one out of 300 patients with HCM that were cared for in Toronto, Canada, who underwent analysis of unreported genes. Ancestry was not reported. Ho et al. (2009) reported this variant in one out of 40 patients with HCM that were cared for in Boston, MA, Minneapolis, MN, and Copenhagen, Denmark, who underwent analysis of at least the MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 genes. Kapplinger et al. (2013) reported this variant in four out of 2,178 patients with HCM that were cared for in Mayo Clinic in Rochester, Minnesota or tested by Transgenomic Inc. Patients underwent analysis of the MYH7, MYL2, MYL3, MYBPC3, ACTC, TNNC1, TNNI3, TNNT2, and TPM1 genes. Patient specific ancestry was not reported. Fokstuen et al. (2008) reported this variant in one out of 8 patients with HCM of unreported ancestry that were cared for in University College London Hospitals, London, United Kingdom. They performed analysis of HCM associated genes including: MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC, TNNC1, and PRKAG2. Probst et al. (2011) reported this variant in one out of 63 LVNC cases of western European ancestry that were cared for in University Hospital Zurich, Switzerland, and the German Heart Institute Berlin, Germany, who underwent analysis of MYH7, ACTC1, TNNT2, TNNI3, MYL2, MYL3, TPM1 and MYBPC3 genes. The proband is a 55-year-old male, who presented with sudden chest pain, dyspnea, pronounced midventricular wall LVNC and increased right ventricular trabeculations. In LMM's summary report submitted to ClinVar (4/10/2014), they note that they have identified this variant in at least 11 presumably unrelated cases of HCM and 3 affected family members (unclear if they are from the same family or different families). These cases likely overlap with others, including those reported by Ho et al. In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts the variant to be not tolerated. Glutamic acid at position 192 is highly conserved in mammals and across evolutionarily distant species. No other variants have been reported in association with disease at this codon. This variant lies in the troponin T binding region of alpha-tropomyosin, as do several other TPM1 variants that have been observed in patients with primary cardiomyopathies (p.Ile172Thr; p.Asp175Asn; p.Glu180Gly; p.Glu180Val; p.Leu185Arg) (Jagatheesan, 2010). It has been suggested that variants in this domain may disrupt calcium signaling and tropomyosin - troponin T binding (Wieczorek, 2008). LMM notes that a computational tool clinically validated by their laboratory predicts this variant to be pathogenic. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan, 2011). In total the variant has not been seen in ~61,476 individuals from published controls and publicly available datasets that approximate the general population. The variant was absent in 60,335 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 22nd, 2015). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population; others were enriche -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 28, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 21, 2023	- -

Hypertrophic cardiomyopathy 3 Pathogenic:3

Pathogenic, no assertion criteria provided	research	Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	-	The TPM1 gene encodes Tropomyosin 1 which involves in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Mutations in TPM1 result in Hypertrophic cardiomyopathy with an autosomal dominant inheritance (OMIM: 115196). -
Pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene have been associated with late-onset disease or incomplete penetrance (PMIDs: 33642254; 32882290, 32731933). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tropomyosin domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals or families with HCM and is the most common TPM1 pathogenic variant associated with HCM (ClinVar, PMIDs: 24510615, 27532257; 21551322, 26960954, 34638741). (SP) 1208 - Inheritance information is currently unavailable for this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign -

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2015	The p.Glu192Lys variant in TPM1 has been reported in more than 20 individuals wi th HCM (Van Driest 2003, Ho 2009, Probst 2011, Deva 2013, Kapplinger 2014, Coppi ni 2014, LMM unpublished data) and segregated with disease in 4 affected relativ es from 4 different families (LMM unpublished data). It is absent from large pop ulation studies. Glutamic acid (Glu) at position 192 is highly conserved in mamm als and across evolutionarily distant species and the change to Lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by o ur laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significa nce. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 192 of the TPM1 protein (p.Glu192Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and left-ventricular non-compaction (LVNC) and HCM (PMID: 18409188, 20031602, 21551322, 23771913, 24510615, 26960954, 27639548). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31882). An algorithm developed specifically for the TPM1 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 21, 2017	This TPM1 Glu192Lys has since been identified in numerous HCM cases and co-segregated in affected family members (Ho CY, et al., 2009; Probst S, et al., 2011; Deva DP, et al., 2013; Kapplinger JD, et al., 2014; Mango R, et al., 2016; ClinVar:SCV000209318, SCV000220120; https://cardiodb.org/ACGV/acgv_variant.php?id=5992). Interestingly, Mango et al., (2016) identified this variant co-segregating with HCM in 4 affected family members who also had signs of Brugada Syndrome. Furthermore, this variant is absent in population databases including the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Glutamic acid (Glu) at position 192 is highly conserved across distantly related species and in silico tools (SIFT, MutationTaster, PolyPhen-2) predict this variant to be disease-causing. We have identified this variant in one HCM patient with moderate asymmetric hypertrophy. There is no family history of HCM or SCD. In summary, based on its absence in the general population, observation in multiple unrelated HCM cases, strong segregation data and in silico predictions, we classify TPM1 Glu192Lys as "pathogenic". -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 13, 2021

- -

Left ventricular noncompaction 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 05, 2015

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The p.E192K pathogenic mutation (also known as c.574G>A), located in coding exon 6 of the TPM1 gene, results from a G to A substitution at nucleotide position 574. The glutamic acid at codon 192 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM) and was shown to co-segregate with disease in one family (Deva DP et al. Radiology. 2013;269:68-76; Coppini R et al. J. Am. Coll. Cardiol. 2014;64:2589-2600; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. Heart. 2015;101:294-301; Mango R et al. Circ. J. 2016;80:938-49; Ross SB et al. Circ Cardiovasc Genet. 2017;10(3):e001671; Walsh R et al. Genet. Med. 2017;19:192-203). This variant has also been detected in one patient with left ventricular noncompaction (LVNC) (Probst S et al. Circ Cardiovasc Genet. 2011;4:367-74). 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)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.;.;.;D
Eigen	Uncertain	0.56
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Uncertain	-2.7	D;D;D;D;.;.;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D;D;D;.;.;D;.;D
Sift4G	Benign	0.065	T;T;T;T;.;.;T;.;T
Polyphen		0.013	B;B;.;.;B;.;.;.;.
Vest4		0.95
MutPred		0.85		.;Gain of ubiquitination at E234 (P = 0.0066);.;.;.;.;.;.;.;
MVP		0.97
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199476315; hg19: chr15-63353922; COSMIC: COSV51260395; COSMIC: COSV51260395;