VCV000043444.29 - ClinVar

NM_001018005.2(TPM1):c.82G>C (p.Asp28His)

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.

(8)

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.

Uncertain significance

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.82G>C (p.Asp28His)

Variation ID: 43444 Accession: VCV000043444.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.2 15: 63042911 (GRCh38) [ NCBI UCSC ] 15: 63335110 (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	Mar 8, 2017	Sep 16, 2024	Apr 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001018005.2:c.82G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018005.1:p.Asp28His	missense
NM_000366.6:c.82G>C	NP_000357.3:p.Asp28His	missense
NM_001018004.2:c.82G>C	NP_001018004.1:p.Asp28His	missense
NM_001018006.2:c.82G>C	NP_001018006.1:p.Asp28His	missense
NM_001018007.2:c.82G>C	NP_001018007.1:p.Asp28His	missense
NM_001018020.2:c.82G>C	NP_001018020.1:p.Asp28His	missense
NM_001301244.2:c.82G>C	NP_001288173.1:p.Asp28His	missense
NM_001365776.1:c.82G>C	NP_001352705.1:p.Asp28His	missense
NM_001365777.1:c.82G>C	NP_001352706.1:p.Asp28His	missense
NM_001365778.1:c.82G>C	NP_001352707.1:p.Asp28His	missense
NM_001365779.1:c.82G>C	NP_001352708.1:p.Asp28His	missense
NC_000015.10:g.63042911G>C
NC_000015.9:g.63335110G>C
NG_007557.1:g.5273G>C
LRG_387:g.5273G>C
LRG_387t1:c.82G>C	LRG_387p1:p.Asp28His

... more HGVS ... less HGVS

Protein change

D28H

Other names

p.D28H:GAC>CAC

Canonical SPDI

NC_000015.10:63042910:G:C

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA018385 dbSNP: rs397516391 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	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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2017	RCV000036364.11
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Feb 18, 2022	RCV000620750.5
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jan 29, 2024	RCV000689264.9
not provided	Uncertain significance (2)	criteria provided, single submitter	Apr 23, 2024	RCV000766945.10
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 8, 2021	RCV001525527.5
Hypertrophic cardiomyopathy 21	Uncertain significance (1)	criteria provided, single submitter	Nov 9, 2022	RCV003447482.1

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 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.
Uncertain significance (Dec 01, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060016.6 First in ClinVar: May 03, 2013 Last updated: Apr 17, 2019	Publications: PubMed (1) PubMed: 27532257 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 2
Uncertain significance (Nov 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001735666.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Comment: This missense variant replaces aspartic acid with histidine at codon 28 of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant … (more) This missense variant replaces aspartic acid with histidine at codon 28 of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/31358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Oct 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002042874.2 First in ClinVar: Dec 29, 2021 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (Jan 29, 2024)	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: SCV000816906.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 27532257‚ 33673806‚ 34495297 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 28 of the TPM1 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 28 of the TPM1 protein (p.Asp28His). This variant is present in population databases (rs397516391, gnomAD 0.06%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or atrial fibrillation (PMID: 27532257, 33673806, 34495297). ClinVar contains an entry for this variant (Variation ID: 43444). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Apr 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209347.10 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: Identified in a patient with early-onset atrial fibrillation (AF) in published literature (PMID: 34495297); Not observed at significant frequency in large population cohorts (gnomAD); In … (more) Identified in a patient with early-onset atrial fibrillation (AF) in published literature (PMID: 34495297); 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; This variant is associated with the following publications: (PMID: 27532257, 33673806, 34699384, 29192238, 33495597, 32481709, 34495297, 37652022) (less)
Uncertain significance (Nov 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 21 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175277.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (3) PubMed: 27532257‚ 33673806‚ 34495297 Comment: The TPM1 c.82G>C variant is classified as a VUS (PS4_Moderate, PM2) The TPM1 c.82G>C variant is a single nucleotide change in exon 1/10 of the … (more) The TPM1 c.82G>C variant is classified as a VUS (PS4_Moderate, PM2) The TPM1 c.82G>C variant is a single nucleotide change in exon 1/10 of the TPM1 gene, which is predicted to change the amino acid aspartic acid at position 28 in the protein, to histidine. The variant has been reported in at least 8 probands with a clinical presentation of hypertrophic cardiomyopathy (PMID#27532257, #33673806, #34495297 and ClinVar) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het) (PM2), is reported in dbSNP (rs397516391), is reported as disease causing in the HGMD database (CM1616794) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar #43444). Segregation studies in at least 5 affected family member may aid in further classification of this variant. (less)
Uncertain significance (Feb 18, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000736927.6 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: The c.82G>C (p.D28H) alteration is located in exon 1 (coding exon 1) of the TPM1 gene. This alteration results from a G to C substitution … (more) The c.82G>C (p.D28H) alteration is located in exon 1 (coding exon 1) of the TPM1 gene. This alteration results from a G to C substitution at nucleotide position 82, causing the aspartic acid (D) at amino acid position 28 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely pathogenic (Oct 11, 2018)	Flagged submission flagged submission (Blueprint Genetics Variant Classification Scheme) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927987.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This missense variant replaces aspartic acid with histidine at codon 28 of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/31358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 28 of the TPM1 protein (p.Asp28His). This variant is present in population databases (rs397516391, gnomAD 0.06%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or atrial fibrillation (PMID: 27532257, 33673806, 34495297). ClinVar contains an entry for this variant (Variation ID: 43444). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Identified in a patient with early-onset atrial fibrillation (AF) in published literature (PMID: 34495297); 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; This variant is associated with the following publications: (PMID: 27532257, 33673806, 34699384, 29192238, 33495597, 32481709, 34495297, 37652022)

Comment:

The TPM1 c.82G>C variant is classified as a VUS (PS4_Moderate, PM2) The TPM1 c.82G>C variant is a single nucleotide change in exon 1/10 of the TPM1 gene, which is predicted to change the amino acid aspartic acid at position 28 in the protein, to histidine. The variant has been reported in at least 8 probands with a clinical presentation of hypertrophic cardiomyopathy (PMID#27532257, #33673806, #34495297 and ClinVar) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het) (PM2), is reported in dbSNP (rs397516391), is reported as disease causing in the HGMD database (CM1616794) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar #43444). Segregation studies in at least 5 affected family member may aid in further classification of this variant.

Comment:

The c.82G>C (p.D28H) alteration is located in exon 1 (coding exon 1) of the TPM1 gene. This alteration results from a G to C substitution at nucleotide position 82, causing the aspartic acid (D) at amino acid position 28 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.	Yoneda ZT	JAMA cardiology	2021	PMID: 34495297
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.	Hathaway J	BMC cardiovascular disorders	2021	PMID: 33673806
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs397516391 ...

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.82G>C (p.Asp28His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516391 ...