NM_001018005.2(TPM1):c.105G>C (p.Arg35Ser) AND Hypertrophic cardiomyopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 27, 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:: RCV000852459.4

Allele description

NM_001018005.2(TPM1):c.105G>C (p.Arg35Ser)

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.105G>C (p.Arg35Ser)

HGVS:

NC_000015.10:g.63042934G>C
NG_007557.1:g.5296G>C
NM_000366.6:c.105G>C
NM_001018004.2:c.105G>C
NM_001018005.2:c.105G>CMANE SELECT
NM_001018006.2:c.105G>C
NM_001018007.2:c.105G>C
NM_001018020.2:c.105G>C
NM_001301244.2:c.105G>C
NM_001365776.1:c.105G>C
NM_001365777.1:c.105G>C
NM_001365778.1:c.105G>C
NM_001365779.1:c.105G>C
NP_000357.3:p.Arg35Ser
NP_001018004.1:p.Arg35Ser
NP_001018005.1:p.Arg35Ser
NP_001018006.1:p.Arg35Ser
NP_001018007.1:p.Arg35Ser
NP_001018020.1:p.Arg35Ser
NP_001288173.1:p.Arg35Ser
NP_001352705.1:p.Arg35Ser
NP_001352706.1:p.Arg35Ser
NP_001352707.1:p.Arg35Ser
NP_001352708.1:p.Arg35Ser
LRG_387t1:c.105G>C
LRG_387:g.5296G>C
LRG_387p1:p.Arg35Ser
NC_000015.9:g.63335133G>C
NC_000015.9:g.63335133G>C
NM_001018005.1:c.105G>C

Protein change:

R35S

Links:

dbSNP: rs1448738061

NCBI 1000 Genomes Browser:

rs1448738061

Molecular consequence:

NM_000366.6:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.105G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.105G>C - 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

Recent activity

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ATP-dependent metallopeptidase FtsH/Yme1/Tma family protein, partial [Burkholder...
ATP-dependent metallopeptidase FtsH/Yme1/Tma family protein, partial [Burkholderia ubonensis]
gi|2810124145|ref|WP_375781542.1|

Protein
phosphoenolpyruvate carboxykinase, partial [Stethorus sp. CO617]
phosphoenolpyruvate carboxykinase, partial [Stethorus sp. CO617]
gi|1047355376|gb|ANW44913.1|

Protein
GAPDHP48 glyceraldehyde 3 phosphate dehydrogenase pseudogene 48 [Homo sapiens]
GAPDHP48 glyceraldehyde 3 phosphate dehydrogenase pseudogene 48 [Homo sapiens]
Gene ID:100240713

Gene
LOC105373417 [Homo sapiens]
LOC105373417 [Homo sapiens]
Gene ID:105373417

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000995153	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 8, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003451146	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004815432	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 27, 2023)	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

SCV000995153

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 8, 2018)

germline

clinical testing

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

SCV003451146

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2021)

germline

clinical testing

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

SCV004815432

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 27, 2023)

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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego, SCV000995153.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV003451146.1

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

Description

This sequence change replaces arginine with serine at codon 35 of the TPM1 protein (p.Arg35Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 691665). 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: "Benign"; Align-GVGD: "Class C0"). 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, SCV004815432.1

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

Description

This missense variant replaces arginine with serine at codon 35 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/218276 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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