rs199476317

Variant names:

• chr15-63062263-G-A
• rs199476317
• NM_001018005.2:c.688G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001018005.2(TPM1):​c.688G>A​(p.Asp230Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.88
• Publications: 35 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• dilated cardiomyopathy 1Y

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 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, 16 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-63062263-G-A is Pathogenic according to our data. Variant chr15-63062263-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.688G>A	p.Asp230Asn	missense_variant	Exon 7 of 10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.688G>A	p.Asp230Asn	missense_variant	Exon 7 of 10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Apr 15, 2012

Leiden Muscular Dystrophy (TPM1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with dilated cardiomyopathy (Lakdawala et al., 2010; Pugh et al., 2014; Walsh et al., 2017); 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; Published functional studies demonstrate a damaging effect as this variant significantly impairs sarcomere function compared to wild-type TPM1 protein (Lakdawala et al., 2010; Memo et al., 2013); This variant is associated with the following publications: (PMID: 23539503, 25548289, 23836688, 25202278, 25241052, 25525159, 21310275, 28166811, 23281406, 25179549, 21483645, 24503780, 27872154, 28600229, 31216405, 31983221, 20117437, 27532257, 34935411) -

Nov 07, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp230Asn (c.688 G>A) in TPM1 The variant has been seen in at least 2 unrelated cases of familial DCM with strong segregation data (not including our patient's family). Lakdawala et al (2010) observed the variant in two Caucasian families with DCM. Ten affected members of one family and 6 affected members of there other family carried the variant. The authors report that 21 of 25 unaffected adult family members did not have the variant. The combined LOD score was 5.22. There was marked intrafamilial variability with some family members diagnosed in the first year of life and others diagnosed in mid-adulthood. The same group later reported on early phenotypes in DCM including individuals with p.Asp230Asn (Lakdawala et al 2012). Presumably these were the same families as their prior report. This is a non-conservative amino acid substitution. The aspartate at codon 230 is conserved across species. PolyPhen predicts the variant to be possibly damaging. Lakdawala et al (2010) assessed the impact of the variant using an in vitro reconstituted sarcomere complex. They found inhibited sarcomere function with reduced calcium sensitivity, maximum activation and calcium affinity. A nearby variant has been reported in association with DCM, p.Ala239Thr (Stenson et al 2009). In total the variants has not been seen in at least 7000 published controls and publicly available general population samples. Lakdawala et al (2010) did not observe the variant in >500 Caucasian individuals. There is no variation at codon 230 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 28th, 2012). The variant is not listed in 1000 genomes (as of October 28th, 2012). It is listed in dbSNP, pointing to an online database for TPM1 variants that cites Lakdawala et al (2010). -

Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y Pathogenic:1

Oct 12, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:1

Oct 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp230Asn variant in TPM1 has been identified in 2 Caucasian individuals w ith DCM and segregated with disease in 14 affected relatives (Lakdawala 2010, LM M unpublished data). This variant was absent from large population studies. In a ddition, in vitro studies supported that this variant impacts contractility (Lak dawala 2010). In summary, the p.Asp230Asn variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based on segregation and abs ence in controls. -

Hypertrophic cardiomyopathy Pathogenic:1

Jul 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 230 of the TPM1 protein (p.Asp230Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20117437, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31884). 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. Experimental studies have shown that this missense change affects TPM1 function (PMID: 23539503, 25242052, 25548289, 28600229, 28603979). For these reasons, this variant has been classified as Pathogenic. -

TPM1-related disorder Pathogenic:1

Feb 26, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.688G>A (p.Asp230Asn) variant affects a moderately conserved amino acid and in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a heterozygous change in patients with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 21310275, 20117437, 25548289, 34935411, 36178741, 36129056). The c.688G>A (p.Asp230Asn) variant in the TPM1 gene was observed to segregate in two families diagnosed with dilated cardiomyopathy (PMID: 20117437). Functional studies indicate this variant reduces calcium sensitivity and inhibits sarcomere function (PMID: 20117437, 23539503, 25241052, 25548289). The c.688G>A (p.Asp230Asn) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.688G>A (p.Asp230Asn) is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;D;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;M;M;M;M;.;.;.;.;.;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;.;D;T;.;D;D;D;T
Sift4G	Benign	0.074	T;T;T;T;T;T;T;.;.;T;T;.;T;D;T;D
Polyphen		0.91, 0.28, 0.25, 0.99	.;.;P;B;.;.;.;B;.;.;.;.;.;D;.;.
Vest4		0.84
MutPred		0.60		.;.;.;Gain of MoRF binding (P = 0.0548);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		2.5
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs199476317; hg19: chr15-63354462;