ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)
Variation ID: 31884 Accession: VCV000031884.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63062263 (GRCh38) [ NCBI UCSC ] 15: 63354462 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.688G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Asp230Asn missense NM_000366.6:c.688G>A NP_000357.3:p.Asp230Asn missense NM_001018004.1:c.688G>A NM_001018004.2:c.688G>A NP_001018004.1:p.Asp230Asn missense NM_001018006.2:c.688G>A NP_001018006.1:p.Asp230Asn missense NM_001018007.2:c.688G>A NP_001018007.1:p.Asp230Asn missense NM_001018008.2:c.580G>A NP_001018008.1:p.Asp194Asn missense NM_001018020.2:c.688G>A NP_001018020.1:p.Asp230Asn missense NM_001301244.2:c.688G>A NP_001288173.1:p.Asp230Asn missense NM_001301289.2:c.580G>A NP_001288218.1:p.Asp194Asn missense NM_001330344.2:c.580G>A NP_001317273.1:p.Asp194Asn missense NM_001330346.2:c.580G>A NP_001317275.1:p.Asp194Asn missense NM_001330351.2:c.580G>A NP_001317280.1:p.Asp194Asn missense NM_001365776.1:c.688G>A NP_001352705.1:p.Asp230Asn missense NM_001365777.1:c.688G>A NP_001352706.1:p.Asp230Asn missense NM_001365778.1:c.814G>A NP_001352707.1:p.Asp272Asn missense NM_001365779.1:c.688G>A NP_001352708.1:p.Asp230Asn missense NM_001365780.1:c.580G>A NP_001352709.1:p.Asp194Asn missense NM_001365781.2:c.580G>A NP_001352710.1:p.Asp194Asn missense NM_001365782.1:c.580G>A NP_001352711.1:p.Asp194Asn missense NC_000015.10:g.63062263G>A NC_000015.9:g.63354462G>A NG_007557.1:g.24625G>A LRG_387:g.24625G>A LRG_387t1:c.688G>A LRG_387p1:p.Asp230Asn - Protein change
- D230N, D194N, D272N
- Other names
- p.D230N:GAC>AAC
- Canonical SPDI
- NC_000015.10:63062262:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
848 | 898 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2015 | RCV000036354.6 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2022 | RCV000024580.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2023 | RCV000695968.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2018 | RCV000850515.1 |
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
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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
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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. |
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Pathogenic
(Mar 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000340451.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Sex: mixed
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Pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1Y
Hypertrophic cardiomyopathy 3
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000992719.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
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Pathogenic
(Nov 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209327.14
First in ClinVar: Feb 24, 2015 Last updated: Dec 11, 2022 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196871.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Oct 13, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060006.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
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, … (more)
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. (less)
Number of individuals with the variant: 10
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Pathogenic
(Dec 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000824509.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 07, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280541.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
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 … (more)
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). (less)
Number of individuals with the variant: 3
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not provided
(Apr 15, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045889.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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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
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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. |
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has functional consequence
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Leiden Muscular Dystrophy (TPM1)
Accession: SCV000045889.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap. | McConnell M | Biochemistry | 2017 | PMID: 28603979 |
The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy. | Lynn ML | Journal of molecular and cellular cardiology | 2017 | PMID: 28600229 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. | Gupte TM | The Journal of biological chemistry | 2015 | PMID: 25548289 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
An epidemiologic investigation of physical activity and breast cancer risk in Africa. | Hou N | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2014 | PMID: 25242052 |
Energy landscapes reveal the myopathic effects of tropomyosin mutations. | Orzechowski M | Archives of biochemistry and biophysics | 2014 | PMID: 25241052 |
Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity. | Memo M | Cardiovascular research | 2013 | PMID: 23539503 |
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. | Jordan DM | American journal of human genetics | 2011 | PMID: 21310275 |
Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy. | Lakdawala NK | Journal of the American College of Cardiology | 2010 | PMID: 20117437 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TPM1 | - | - | - | - |
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Text-mined citations for rs199476317 ...
HelpRecord last updated Aug 25, 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.