NM_001018005.2(TPM1):c.850A>G (p.Ile284Val) AND Cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001186001.6

Allele description [Variation Report for NM_001018005.2(TPM1):c.850A>G (p.Ile284Val)]

NM_001018005.2(TPM1):c.850A>G (p.Ile284Val)

Gene:

TPM1:tropomyosin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.2

Genomic location:

Preferred name:

NM_001018005.2(TPM1):c.850A>G (p.Ile284Val)

Other names:

p.I284V:ATA>GTA

HGVS:

NC_000015.10:g.63064141A>G
NG_007557.1:g.26503A>G
NM_000366.6:c.850A>G
NM_001018004.2:c.772+1496A>G
NM_001018005.2:c.850A>GMANE SELECT
NM_001018006.2:c.772+1496A>G
NM_001018007.2:c.772+1496A>G
NM_001018008.2:c.664+1496A>G
NM_001018020.2:c.772+1496A>G
NM_001301244.2:c.850A>G
NM_001301289.2:c.664+1496A>G
NM_001330344.2:c.664+1496A>G
NM_001330346.2:c.742A>G
NM_001330351.2:c.664+1496A>G
NM_001365776.1:c.772+1496A>G
NM_001365777.1:c.772+1496A>G
NM_001365778.1:c.898+1496A>G
NM_001365779.1:c.850A>G
NM_001365780.1:c.664+1496A>G
NM_001365781.2:c.742A>G
NM_001365782.1:c.742A>G
NP_000357.3:p.Met284Val
NP_001018005.1:p.Ile284Val
NP_001288173.1:p.Ile284Val
NP_001317275.1:p.Ile248Val
NP_001352708.1:p.Met284Val
NP_001352710.1:p.Met248Val
NP_001352711.1:p.Met248Val
LRG_387t1:c.850A>G
LRG_387:g.26503A>G
LRG_387p1:p.Ile284Val
NC_000015.9:g.63356340A>G
NM_000366.5:c.850A>G
NM_001018005.1:c.850A>G
NM_001301244.1:c.850A>G
p.(Ile284Val)
r.(spl?)

Protein change:

I248V

Links:

Leiden Muscular Dystrophy (TPM1): TPM1_00029; dbSNP: rs199476322

NCBI 1000 Genomes Browser:

rs199476322

Molecular consequence:

NM_001018004.2:c.772+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018006.2:c.772+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018007.2:c.772+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018008.2:c.664+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018020.2:c.772+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001301289.2:c.664+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001330344.2:c.664+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001330351.2:c.664+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365776.1:c.772+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365777.1:c.772+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365778.1:c.898+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365780.1:c.664+1496A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000366.6:c.850A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.850A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.850A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.742A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.850A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.742A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.742A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001352326	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 19, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18533079, 20159828, 23674513, 25031304, 27532257, 30240712, 30847666, 25741868
SCV003838600	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001352326

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 19, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV003838600

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 14, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy.

Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F.

Mayo Clin Proc. 2008 Jun;83(6):630-8. doi: 10.4065/83.6.630.

PubMed [citation]

PMID:: 18533079

Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.

Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM.

Circulation. 2010 Mar 2;121(8):997-1004. doi: 10.1161/CIRCULATIONAHA.109.904557. Epub 2010 Feb 16.

PubMed [citation]

PMID:: 20159828
PMCID:: PMC2857348

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001352326.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces isoleucine with valine at codon 284 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not have significant effects on protein function and interaction with actin (PMID: 30240712). This variant has been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20159828, 23674513, 25031304, 27532257, 30847666), and in one individual with non-compaction cardiomyopathy (PMID: 30847666). This variant has not been identified 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV003838600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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