rs104894503
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong
The NM_001018005.2(TPM1):โc.523G>Aโ(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 (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D175G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.523G>A | p.Asp175Asn | missense_variant | 5/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.523G>A | p.Asp175Asn | missense_variant | 5/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251400Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135872
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727220
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74358
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | In 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 provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Jun 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Aug 25, 2023 | - - |
Hypertrophic cardiomyopathy Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 03, 2016 | The 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 submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This 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 submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jan 05, 2024 | This sequence change in TPM1 is predicted to replace aspartic acid with asparagine at codon 175, p.(Asp175Asn). The aspartic acid residue is highly conserved (100 vertebrates, Multiz alignments), and is located in the coiled-coil domain. There is a small physicochemical difference between aspartic acid and asparagine. TPM1, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (8/64,018 alleles) in the Finnish population, while the highest population frequency in a non-bottlenecked population is 0.0003% (4/1,180,052 alleles) in the European (non-Finnish) population. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy and is the reported founder mutation in the Finnish population and segregates with cardiomyopathy in multiple unrelated families (PMID: 9822100, 22462493). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with hypertrophic cardiomyopathy (PMID: 7729014). An in vitro functional assay in heart muscle fibres and a transgenic mouse model expressing this variant in the heart showed an increase in calcium ion (Ca2+) sensitivity (PMID: 9440709, 10400910). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.785). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4, PM2_Supporting, PS2_Supporting, PP2, PP3, PS3_Moderate. - |
Hypertrophic cardiomyopathy 3 Pathogenic:3Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 11, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | May 24, 2023 | - - |
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2019 | This 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. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 04, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2015 | - - |
Dilated cardiomyopathy 1Y Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This 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 submitter | clinical testing | Ambry Genetics | Dec 15, 2023 | The c.523G>A (p.D175N) alteration is located in exon 5 (coding exon 5) of the TPM1 gene. This alteration results from a G to A substitution at nucleotide position 523, causing the aspartic acid (D) at amino acid position 175 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/282804) total alleles studied. The highest observed frequency was 0.016% (4/25076) of European (Finnish) alleles. 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, 1995; Jääskeläinen, 2004; Hedman, 2004; Jääskeläinen, 2013). This amino acid position is well conserved in available vertebrate species. 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, 1998; Ly, 2012; Robinson, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at