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.
ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(21)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
21
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)
Variation ID: 12456 Accession: VCV000012456.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q22.2 15: 63060899 (GRCh38) [ NCBI UCSC ] 15: 63353098 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Aug 25, 2024 Jan 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001018005.2:c.523G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Asp175Asn missense NM_000366.6:c.523G>A NP_000357.3:p.Asp175Asn missense NM_001018004.2:c.523G>A NP_001018004.1:p.Asp175Asn missense NM_001018006.2:c.523G>A NP_001018006.1:p.Asp175Asn missense NM_001018007.2:c.523G>A NP_001018007.1:p.Asp175Asn missense NM_001018008.2:c.415G>A NP_001018008.1:p.Asp139Asn missense NM_001018020.2:c.523G>A NP_001018020.1:p.Asp175Asn missense NM_001301244.2:c.523G>A NP_001288173.1:p.Asp175Asn missense NM_001301289.2:c.415G>A NP_001288218.1:p.Asp139Asn missense NM_001330344.2:c.415G>A NP_001317273.1:p.Asp139Asn missense NM_001330346.2:c.415G>A NP_001317275.1:p.Asp139Asn missense NM_001330351.2:c.415G>A NP_001317280.1:p.Asp139Asn missense NM_001365776.1:c.523G>A NP_001352705.1:p.Asp175Asn missense NM_001365777.1:c.523G>A NP_001352706.1:p.Asp175Asn missense NM_001365778.1:c.649G>A NP_001352707.1:p.Asp217Asn missense NM_001365779.1:c.523G>A NP_001352708.1:p.Asp175Asn missense NM_001365780.1:c.415G>A NP_001352709.1:p.Asp139Asn missense NM_001365781.2:c.415G>A NP_001352710.1:p.Asp139Asn missense NM_001365782.1:c.415G>A NP_001352711.1:p.Asp139Asn missense NC_000015.10:g.63060899G>A NC_000015.9:g.63353098G>A NG_007557.1:g.23261G>A LRG_387:g.23261G>A LRG_387t1:c.523G>A LRG_387p1:p.Asp175Asn P09493:p.Asp175Asn - Protein change
- D175N, D139N, D217N
- Other names
-
p.D175N:GAC>AAC
- Canonical SPDI
- NC_000015.10:63060898:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functional variant; Sequence Ontology [ SO:0001536]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
856 | 904 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Nov 4, 2015 | RCV000036340.8 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 24, 2023 | RCV000013272.29 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Aug 25, 2023 | RCV000159366.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2016 | RCV001197088.3 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2024 | RCV000474684.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2022 | RCV001170568.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV000622165.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001346437.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Feb 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 3
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579831.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM2_SUP, PP3
|
Number of individuals with the variant: 2
Sex: male
|
|
|
Pathogenic
(Feb 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209312.14
First in ClinVar: Feb 24, 2015 Last updated: Apr 23, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(May 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 3
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
|
KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV003925778.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Sex: male
|
|
|
Pathogenic
(Oct 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333156.4
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198857.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Nov 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000188839.4
First in ClinVar: Sep 07, 2014 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 9
|
|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747373.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
|
|
|
Pathogenic
(May 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059992.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 15
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1Y
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367724.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3.
|
|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762138.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Hypertrophic cardiomyopathy (present)
Sex: female
|
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000547697.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812546.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740009.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956834.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966578.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Apr 03, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Hypertrophic Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053302.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2015 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922946.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929241.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Pathogenic
(May 01, 1995)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033519.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In members of family MI with a form of familial hypertrophic cardiomyopathy linked to 15q (CMH3; 115196), Thierfelder et al. (1994) found heterozygosity for a … (more)
In members of family MI with a form of familial hypertrophic cardiomyopathy linked to 15q (CMH3; 115196), Thierfelder et al. (1994) found heterozygosity for a G-to-A transition at nucleotide 579 that altered codon 175 from GAC to AAC. The substitution predicted that the mutated allele present in affected individuals would encode a neutral asparagine residue instead of the negatively charged aspartic acid residue found in unaffected individuals. Watkins et al. (1995) investigated whether the D175N mutation was really responsible for hypertrophic cardiomyopathy or was only a polymorphism, because some features of the 2 identified mutations in the alpha-tropomyosin gene contrasted with those of mutations in other disease genes for CMH. Unlike the beta-cardiac myosin heavy chain gene (MYH7; 160760) and the cardiac troponin-T gene, the alpha-tropomyosin gene is expressed ubiquitously, yet the disease phenotype is limited to cardiac muscle. Watkins et al. (1995) found that the D175N mutation was present in the proband and 2 affected offspring, but in none of the proband's 3 sibs. Although both parents were deceased, the haplotypes of the 4 parental chromosomes could be reconstructed. (The haplotypes made use of an intragenic polymorphism in 10 flanking polymorphisms spanning a region of 35 cM.) One parental chromosome was transmitted to 2 offspring: 1 bearing the D175N mutation (the affected proband) and 1 clinically unaffected sib who lacked the mutation. Thus the D175N mutation must have arisen de novo. (less)
|
|
|
not provided
(Apr 15, 2012)
|
no classification provided
Method: curation
|
Familial hypertrophic cardiomyopathy 3
Affected status: not provided
Allele origin:
germline
|
Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045883.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
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)
Comment:
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.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3.
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
has functional consequence
|
Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045883.1
|
|
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3.
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Hypertrophic cardiomyopathy mutations increase myofilament Ca(2+) buffering, alter intracellular Ca(2+) handling, and stimulate Ca(2+)-dependent signaling. | Robinson P | The Journal of biological chemistry | 2018 | PMID: 29760186 |
| Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. | Gupte TM | The Journal of biological chemistry | 2015 | PMID: 25548289 |
| Two founder mutations in the alpha-tropomyosin and the cardiac myosin-binding protein C genes are common causes of hypertrophic cardiomyopathy in the Finnish population. | Jääskeläinen P | Annals of medicine | 2013 | PMID: 22462493 |
| Long-range effects of familial hypertrophic cardiomyopathy mutations E180G and D175N on the properties of tropomyosin. | Ly S | Biochemistry | 2012 | PMID: 22794249 |
| The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy. | Li XE | Biochemical and biophysical research communications | 2012 | PMID: 22789852 |
| The effect of the Asp175Asn and Glu180Gly TPM1 mutations on actin-myosin interaction during the ATPase cycle. | Rysev NA | Biochimica et biophysica acta | 2012 | PMID: 22155441 |
| Facilitated cross-bridge interactions with thin filaments by familial hypertrophic cardiomyopathy mutations in α-tropomyosin. | Wang F | Journal of biomedicine & biotechnology | 2011 | PMID: 22187526 |
| Hypertrophic cardiomyopathy-causing Asp175asn and Glu180gly Tpm1 mutations shift tropomyosin strands further towards the open position during the ATPase cycle. | Borovikov YS | Biochemical and biophysical research communications | 2011 | PMID: 21376702 |
| Enhanced active cross-bridges during diastole: molecular pathogenesis of tropomyosin's HCM mutations. | Bai F | Biophysical journal | 2011 | PMID: 21320446 |
| Several cardiomyopathy causing mutations on tropomyosin either destabilize the active state of actomyosin or alter the binding properties of tropomyosin. | Mathur MC | Biochemical and biophysical research communications | 2011 | PMID: 21295541 |
| Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes. | Poutanen T | American heart journal | 2006 | PMID: 16504640 |
| Cine MR imaging of myocardial contractile impairment in patients with hypertrophic cardiomyopathy attributable to Asp175Asn mutation in the alpha-tropomyosin gene. | Sipola P | Radiology | 2005 | PMID: 16014439 |
| Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes. | Jääskeläinen P | Annals of medicine | 2004 | PMID: 15000344 |
| Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene. | Hedman A | Journal of molecular and cellular cardiology | 2004 | PMID: 14734051 |
| Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. | Van Driest SL | Circulation | 2002 | PMID: 12473556 |
| Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region. | Palm T | Biophysical journal | 2001 | PMID: 11606294 |
| Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha -tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay. | Bing W | Journal of molecular and cellular cardiology | 2000 | PMID: 10900175 |
| Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. | Muthuchamy M | Circulation research | 1999 | PMID: 10400910 |
| The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population. | Jääskeläinen P | Journal of the American College of Cardiology | 1998 | PMID: 9822100 |
| A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. | Bottinelli R | Circulation research | 1998 | PMID: 9440709 |
| Effects of two hypertrophic cardiomyopathy mutations in alpha-tropomyosin, Asp175Asn and Glu180Gly, on Ca2+ regulation of thin filament motility. | Bing W | Biochemical and biophysical research communications | 1997 | PMID: 9245729 |
| Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene. | Coviello DA | Journal of the American College of Cardiology | 1997 | PMID: 9060904 |
| Novel missense mutation in alpha-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. | Nakajima-Taniguchi C | Journal of molecular and cellular cardiology | 1995 | PMID: 8523464 |
| Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. | Watkins H | The New England journal of medicine | 1995 | PMID: 7898523 |
| A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy. | Watkins H | Circulation | 1995 | PMID: 7729014 |
| Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. | Thierfelder L | Cell | 1994 | PMID: 8205619 |
| click to load more click to collapse | ||||
Text-mined citations for rs104894503 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.