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rs104894503

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_001018005.2(TPM1):c.523G>A(p.Asp175Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,042 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D175G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

12
5
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001018005.2
PP2
Missense variant where missense usually causes diseases, TPM1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903
PP5
Variant 15-63060899-G-A is Pathogenic according to our data. Variant chr15-63060899-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63060899-G-A is described in Lovd as [Pathogenic]. Variant chr15-63060899-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TPM1NM_001018005.2 linkuse as main transcriptc.523G>A p.Asp175Asn missense_variant 5/10 ENST00000403994.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TPM1ENST00000403994.9 linkuse as main transcriptc.523G>A p.Asp175Asn missense_variant 5/101 NM_001018005.2 A1P09493-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251400
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461844
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727220
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:
0.0000116
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 24, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Several published functional studies have shown the deleterious effects of p.(D175N) (Muthuchamy et al., 1999; Mathur et al., 2011; Ly et al., 2012; Sewanan et al., 2016), including an in vitro study performed by Bottinelli et al., 1998, that showed that p.(D175N) results in increased calcium sensitivity; This variant is associated with the following publications: (PMID: 32217077, 15000344, 8523464, 16504640, 9822100, 12473556, 16014439, 27833562, 7729014, 31270709, 30775854, 22462493, 22155441, 21295541, 21376702, 22789852, 9245729, 10900175, 22794249, 21320446, 22187526, 25241052, 10400910, 23283745, 8205619, 21310275, 27878731, 27532257, 28166811, 29915098, 29760186, 8774330, 9060904, 11606294, 7898523, 30165862, 30923661, 31643006, 14734051, 9440709, 33906374, 33673806, 35653365, 28193612) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenJun 17, 2021- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Hypertrophic cardiomyopathy 3 Pathogenic:3Other:1
not provided, no classification providedcurationLeiden Muscular Dystrophy (TPM1)Apr 15, 2012- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 11, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 1995- -
Pathogenic, criteria provided, single submitterclinical testingKardioGenetik, Herz- und Diabeteszentrum NRWMay 24, 2023- -
Hypertrophic cardiomyopathy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 17, 2024This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 175 of the TPM1 protein (p.Asp175Asn). This variant is present in population databases (rs104894503, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) in many families, and is a common cause of HCM in Finland (PMID: 7729014, 8205619, 9060904, 22462493, 25548289). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12456). 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: 9245729, 10400910, 10900175, 22155441). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 03, 2016The p.Asp175Asn variant in TPM1 has been reported in multiple individuals with H CM, segregated with disease in more than 15 families, and occurred de novo in at least 1 individual (Thierfelder 1994, Nakajima-Taniguchi 1995, Watkins 1995, Co viello 1997, Van Driest 2002, Hedman 2004, Sipola 2005, Poutanen 2006, Jaaskelai nen 2013). It was also absent from large population studies. Additionally, funct ional studies support a pathogenic role for this variant (Bottinelli 1998, Muthu chamy 1999, Mathur 2011, Bai 2011, Borovikov 2011, Wang 2011, Li 2012, Ly 2012, Rysev 2012). In summary, the p.Asp175Asn variant meets our criteria to be classi fied as pathogenic for HCM in an autosomal dominant manner based on segregation studies and functional evidence. -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 10, 2019This missense variant replaces aspartic acid with asparagine at codon 175 of the TPM1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant increases calcium sensitivity, sliding velocity and the bending flexibility of the thin filaments (PMID: 9245729, 10900175, 22789852, 22794249, 29361520, 30923661). Transgenic mouse expressing this variant only in heart exhibited myocardial functional impairment and histologic structural changes as in the human form of the disease (PMID: 10400910). This variant is a common founder mutation in Finnish population and has been reported in many individuals affected with hypertrophic cardiomyopathy (PMID: 7729014, 8205619, 8523464, 9060904, 14734051, 15000344, 16014439, 16504640, 22239901, 22462493). It has been shown that this variant segregates with the disease in at least three families (PMID: 7729014, 8205619, 9060904). This variant has been identified in 5/282804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioOct 04, 2022- -
Primary familial hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 04, 2015- -
Pathogenic, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 03, 2015- -
Dilated cardiomyopathy 1Y Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 15, 2023The p.D175N pathogenic mutation (also known as c.523G>A), located in coding exon 5 of the TPM1 gene, results from a G to A substitution at nucleotide position 523. The aspartic acid at codon 175 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM). It was initially described in a cohort of Finnish families with HCM with evidence that it stemmed from a common ancestor, although a case of probable de novo occurrence was reported (Watkins H et al. Circulation. 1995;91:2302-5, Jääskeläinen P et al. Ann Med. 2004;36(1):23-32, Hedman A et al. J Mol Cell Cardiol. 2004;36:91-9, Jääskeläinen P et al. Ann Med. 2013;45:85-90). Functional studies have shown the presence of this alteration affected local stability of the tropomyosin 1 protein and increased calcium sensitivity and residual ATPase activity, with impact on calcium-dependent signaling cascades (Bottinelli R et al. Circ Res 1998;82:106-15; Ly S et al. Biochemistry. 2012;51:6413-20; Robinson P et al. J. Biol. Chem., 2018 07;293:10487-10499). 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
0.51
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
Cadd
Pathogenic
29
Dann
Uncertain
1.0
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.79
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Pathogenic
0.73
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
3.3
M;M;M;.;M;M;M;M;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.6
D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
Sift4G
Uncertain
0.046
D;T;D;T;T;T;T;.;.;T;T;.;T;D;T;T
Polyphen
0.24, 0.89, 0.092, 0.73
.;.;B;P;.;.;.;B;.;.;.;.;.;P;.;.
Vest4
0.87
MutPred
0.81
.;.;.;Gain of MoRF binding (P = 0.0534);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.96
MPC
2.3
ClinPred
0.91
D
GERP RS
5.8
Varity_R
0.56
gMVP
0.95

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.

Other links and lift over

dbSNP: rs104894503; hg19: chr15-63353098; API