NM_001018005.2(TPM1):c.253G>A (p.Val85Ile) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 2, 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:: RCV000534139.7

Allele description [Variation Report for NM_001018005.2(TPM1):c.253G>A (p.Val85Ile)]

NM_001018005.2(TPM1):c.253G>A (p.Val85Ile)

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.253G>A (p.Val85Ile)

HGVS:

NC_000015.10:g.63056997G>A
NG_007557.1:g.19359G>A
NM_000366.6:c.253G>A
NM_001018004.2:c.253G>A
NM_001018005.2:c.253G>AMANE SELECT
NM_001018006.2:c.253G>A
NM_001018007.2:c.253G>A
NM_001018008.2:c.145G>A
NM_001018020.2:c.253G>A
NM_001301244.2:c.253G>A
NM_001301289.2:c.145G>A
NM_001330344.2:c.145G>A
NM_001330346.2:c.145G>A
NM_001330351.2:c.145G>A
NM_001365776.1:c.253G>A
NM_001365777.1:c.253G>A
NM_001365778.1:c.379G>A
NM_001365779.1:c.253G>A
NM_001365780.1:c.145G>A
NM_001365781.2:c.145G>A
NM_001365782.1:c.145G>A
NP_000357.3:p.Val85Ile
NP_001018004.1:p.Val85Ile
NP_001018005.1:p.Val85Ile
NP_001018006.1:p.Val85Ile
NP_001018007.1:p.Val85Ile
NP_001018008.1:p.Val49Ile
NP_001018020.1:p.Val85Ile
NP_001288173.1:p.Val85Ile
NP_001288218.1:p.Val49Ile
NP_001317273.1:p.Val49Ile
NP_001317275.1:p.Val49Ile
NP_001317280.1:p.Val49Ile
NP_001352705.1:p.Val85Ile
NP_001352706.1:p.Val85Ile
NP_001352707.1:p.Val127Ile
NP_001352708.1:p.Val85Ile
NP_001352709.1:p.Val49Ile
NP_001352710.1:p.Val49Ile
NP_001352711.1:p.Val49Ile
LRG_387t1:c.253G>A
LRG_387:g.19359G>A
LRG_387p1:p.Val85Ile
NC_000015.9:g.63349196G>A
NM_001018005.1:c.253G>A

Protein change:

V127I

Links:

dbSNP: rs730881156

NCBI 1000 Genomes Browser:

rs730881156

Molecular consequence:

NM_000366.6:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018008.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301289.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330344.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330351.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.379G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365780.1:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.145G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000623799	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29121657, 28492532
SCV004815441	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29121657, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000623799

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 10, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004815441

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Viswanathan SK, Sanders HK, McNamara JW, Jagadeesan A, Jahangir A, Tajik AJ, Sadayappan S.

PLoS One. 2017;12(11):e0187948. doi: 10.1371/journal.pone.0187948.

PubMed [citation]

PMID:: 29121657
PMCID:: PMC5679632

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000623799.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 85 of the TPM1 protein (p.Val85Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181683). 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.

#	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 All of Us Research Program, National Institutes of Health, SCV004815441.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces valine with isoleucine at codon 85 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 a familial case of hypertrophic cardiomyopathy with two carriers (PMID: 29121657). 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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