VCV000043420.23 - ClinVar

NM_001018005.2(TPM1):c.475G>A (p.Asp159Asn)

Germline

Classification

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.

(9)

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/Likely pathogenic

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.475G>A (p.Asp159Asn)

Variation ID: 43420 Accession: VCV000043420.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.2 15: 63059663 (GRCh38) [ NCBI UCSC ] 15: 63351862 (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	Jan 31, 2015	Feb 14, 2024	Jul 25, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018005.2:c.475G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018005.1:p.Asp159Asn	missense
NM_000366.6:c.475G>A	NP_000357.3:p.Asp159Asn	missense
NM_001018004.2:c.475G>A	NP_001018004.1:p.Asp159Asn	missense
NM_001018006.2:c.475G>A	NP_001018006.1:p.Asp159Asn	missense
NM_001018007.2:c.475G>A	NP_001018007.1:p.Asp159Asn	missense
NM_001018008.2:c.367G>A	NP_001018008.1:p.Asp123Asn	missense
NM_001018020.2:c.475G>A	NP_001018020.1:p.Asp159Asn	missense
NM_001301244.2:c.475G>A	NP_001288173.1:p.Asp159Asn	missense
NM_001301289.2:c.367G>A	NP_001288218.1:p.Asp123Asn	missense
NM_001330344.2:c.367G>A	NP_001317273.1:p.Asp123Asn	missense
NM_001330346.2:c.367G>A	NP_001317275.1:p.Asp123Asn	missense
NM_001330351.2:c.367G>A	NP_001317280.1:p.Asp123Asn	missense
NM_001365776.1:c.475G>A	NP_001352705.1:p.Asp159Asn	missense
NM_001365777.1:c.475G>A	NP_001352706.1:p.Asp159Asn	missense
NM_001365778.1:c.601G>A	NP_001352707.1:p.Asp201Asn	missense
NM_001365779.1:c.475G>A	NP_001352708.1:p.Asp159Asn	missense
NM_001365780.1:c.367G>A	NP_001352709.1:p.Asp123Asn	missense
NM_001365781.2:c.367G>A	NP_001352710.1:p.Asp123Asn	missense
NM_001365782.1:c.367G>A	NP_001352711.1:p.Asp123Asn	missense
NC_000015.10:g.63059663G>A
NC_000015.9:g.63351862G>A
NG_007557.1:g.22025G>A
LRG_387:g.22025G>A
LRG_387t1:c.475G>A	LRG_387p1:p.Asp159Asn

... more HGVS ... less HGVS

Protein change

D159N, D123N, D201N

Other names

p.D159N:GAC>AAC
TPM1, ASP159ASN (rs397516373)

Canonical SPDI

NC_000015.10:63059662:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA018069 OMIM: 191010.0008 dbSNP: rs397516373 VarSome

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
Gene	OMIM	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	854	902

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.
Primary dilated cardiomyopathy	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 21, 2017	RCV000036335.6
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2022	RCV000159410.6
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Nov 19, 2019	RCV000722121.3
Dilated cardiomyopathy 1Y	no classifications from unflagged records (1)	no classifications from unflagged records	Oct 31, 2023	RCV000679884.3
Left ventricular noncompaction 9	Pathogenic (1)	no assertion criteria provided	Jan 18, 2023	RCV000736013.2
Hypertrophic cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2022	RCV000694039.10
Hypertrophic cardiomyopathy 3	Likely pathogenic (1)	criteria provided, single submitter	May 30, 2018	RCV001334675.1
Familial cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Mar 31, 2022	RCV002470728.2

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.
Likely pathogenic (Oct 11, 2011)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Primary dilated cardiomyopathy Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059987.6 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Number of individuals with the variant: 1
Pathogenic (Nov 19, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696597.3 First in ClinVar: Feb 24, 2015 Last updated: Feb 03, 2020	Publications: PubMed (5) PubMed: 27177193‚ 27532257‚ 29517769‚ 28359939‚ 29024827 Comment: Variant Summary: TPM1 c.475G>A (p.Asp159Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant Summary: TPM1 c.475G>A (p.Asp159Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251370 control chromosomes (gnomAD). c.475G>A has been reported in the literature in individuals affected with Cardiomyopathy, including two cases in which the mutation was identified as de-novo in children affected with Ebstein anomaly and left ventricular noncompaction (Kelle_2016) and dilated cardiomyopathy with left ventricular hypertophy (Herkert_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters (evaluation after 2014) have cited the variant four times as pathogenic/likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was re-classified as pathogenic. (less)
Likely pathogenic (May 30, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 3 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001527582.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jun 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209356.14 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar … (more) Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available; This variant is associated with the following publications: (PMID: 29024827, 27532257, 28359939, 31737537, Kopylova 2021[poster], 27177193, 29517769) (less)
Pathogenic (Jul 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000822465.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 27177193‚ 27532257 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43420). This missense change has been observed in individual(s) with cardiomyopathy and Ebstein anomaly, left ventricular noncompaction cardiomyopathy (LVNC), and end-stage heart failure and hypertrophic cardiomyopathy (PMID: 27177193, 27532257; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 159 of the TPM1 protein (p.Asp159Asn). (less)
Likely pathogenic (Aug 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995155.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768483.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 27177193‚ 27532257‚ 29517769‚ 31270709 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tropomyosin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with cardiomyopathies (DCM, HCM and Ebstein anomaly of the tricuspid valve which can be associated with left ventricular non-compaction), including de novo reports (ClinVar, LOVD, PMID: 29517769, 27177193, 27532257). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jan 18, 2023)	no assertion criteria provided Method: literature only	LEFT VENTRICULAR NONCOMPACTION 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000864233.2 First in ClinVar: Jan 22, 2019 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 27177193 Comment on evidence: In a 2-year-old girl with severe heart failure and left ventricular noncompaction (LVNC9; see 611878), who also exhibited Ebstein anomaly of the tricuspid valve, Kelle … (more) In a 2-year-old girl with severe heart failure and left ventricular noncompaction (LVNC9; see 611878), who also exhibited Ebstein anomaly of the tricuspid valve, Kelle et al. (2016) identified heterozygosity for a de novo c.475G-A transition (c.475G-A, NM_001018005.1) in exon 4 of the TPM1 gene, resulting in an asp159-to-asn (D159N) substitution at a highly conserved residue adjacent to a likely actin-binding site. The mutation was not found in her unaffected parents or in the ExAC database. The authors stated that the mutation had previously been identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature. (less)
Uncertain significance (Sep 01, 2017)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Clinical significance appears to be a case-level interpretation inconsistent with variant classification Source: ClinGen	Dilated cardiomyopathy 1Y (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV000807281.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 25326635 Comment: This variant was found once in our laboratory de novo in a 1-year-old female with left ventricular noncompaction, hypotonia, failure to thrive, developmental delay, and … (more) This variant was found once in our laboratory de novo in a 1-year-old female with left ventricular noncompaction, hypotonia, failure to thrive, developmental delay, and microcephaly. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Variant Summary: TPM1 c.475G>A (p.Asp159Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251370 control chromosomes (gnomAD). c.475G>A has been reported in the literature in individuals affected with Cardiomyopathy, including two cases in which the mutation was identified as de-novo in children affected with Ebstein anomaly and left ventricular noncompaction (Kelle_2016) and dilated cardiomyopathy with left ventricular hypertophy (Herkert_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters (evaluation after 2014) have cited the variant four times as pathogenic/likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was re-classified as pathogenic.

Comment:

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available; This variant is associated with the following publications: (PMID: 29024827, 27532257, 28359939, 31737537, Kopylova 2021[poster], 27177193, 29517769)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43420). This missense change has been observed in individual(s) with cardiomyopathy and Ebstein anomaly, left ventricular noncompaction cardiomyopathy (LVNC), and end-stage heart failure and hypertrophic cardiomyopathy (PMID: 27177193, 27532257; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 159 of the TPM1 protein (p.Asp159Asn).

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tropomyosin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with cardiomyopathies (DCM, HCM and Ebstein anomaly of the tricuspid valve which can be associated with left ventricular non-compaction), including de novo reports (ClinVar, LOVD, PMID: 29517769, 27177193, 27532257). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1.	Moraczewska J	Journal of muscle research and cell motility	2020	PMID: 31270709
Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy.	Herkert JC	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29517769
Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation.	Nijak A	European journal of medical genetics	2018	PMID: 29024827
Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects.	England J	Journal of molecular and cellular cardiology	2017	PMID: 28359939
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
Ebstein anomaly, left ventricular non-compaction, and early onset heart failure associated with a de novo α-tropomyosin gene mutation.	Kelle AM	American journal of medical genetics. Part A	2016	PMID: 27177193

Text-mined citations for rs397516373 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_001018005.2(TPM1):c.475G>A (p.Asp159Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516373 ...