NM_001018005.2(TPM1):c.457C>G (p.His153Asp) AND Hypertrophic cardiomyopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 6, 2018
Review status:: criteria provided, conflicting classifications

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:: RCV000527568.15

Allele description [Variation Report for NM_001018005.2(TPM1):c.457C>G (p.His153Asp)]

NM_001018005.2(TPM1):c.457C>G (p.His153Asp)

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.457C>G (p.His153Asp)

HGVS:

NC_000015.10:g.63059645C>G
NG_007557.1:g.22007C>G
NM_000366.6:c.457C>G
NM_001018004.2:c.457C>G
NM_001018005.2:c.457C>GMANE SELECT
NM_001018006.2:c.457C>G
NM_001018007.2:c.457C>G
NM_001018008.2:c.349C>G
NM_001018020.2:c.457C>G
NM_001301244.2:c.457C>G
NM_001301289.2:c.349C>G
NM_001330344.2:c.349C>G
NM_001330346.2:c.349C>G
NM_001330351.2:c.349C>G
NM_001365776.1:c.457C>G
NM_001365777.1:c.457C>G
NM_001365778.1:c.583C>G
NM_001365779.1:c.457C>G
NM_001365780.1:c.349C>G
NM_001365781.2:c.349C>G
NM_001365782.1:c.349C>G
NP_000357.3:p.His153Asp
NP_001018004.1:p.His153Asp
NP_001018005.1:p.His153Asp
NP_001018006.1:p.His153Asp
NP_001018007.1:p.His153Asp
NP_001018008.1:p.His117Asp
NP_001018020.1:p.His153Asp
NP_001288173.1:p.His153Asp
NP_001288218.1:p.His117Asp
NP_001317273.1:p.His117Asp
NP_001317275.1:p.His117Asp
NP_001317280.1:p.His117Asp
NP_001352705.1:p.His153Asp
NP_001352706.1:p.His153Asp
NP_001352707.1:p.His195Asp
NP_001352708.1:p.His153Asp
NP_001352709.1:p.His117Asp
NP_001352710.1:p.His117Asp
NP_001352711.1:p.His117Asp
LRG_387t1:c.457C>G
LRG_387:g.22007C>G
LRG_387p1:p.His153Asp
NC_000015.9:g.63351844C>G
NM_000366.5:c.457C>G
NM_001018005.1:c.457C>G
c.457C>G

Protein change:

H117D

Links:

dbSNP: rs397516372

NCBI 1000 Genomes Browser:

rs397516372

Molecular consequence:

NM_000366.6:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018008.2:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001301289.2:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330344.2:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330351.2:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.583C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.457C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365780.1:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.349C>G - 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
SCV000059985	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jan 16, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000623804	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 6, 2018)	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

SCV000059985

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jan 16, 2014)

germline

clinical testing

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

SCV000623804

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 6, 2018)

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	not provided	4	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059985.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

The His153Asp variant in TPM1 has been identified by our laboratory in 1 Caucasi an individual with HCM and segregated with disease in 2 affected relatives. It w as not identified in large population studies. Histidine (His) at position 153 i s highly conserved in mammals and across evolutionarily distant species and the change to aspartic acid (Asp) was predicted to be pathogenic using a computation al tool clinically validated by our laboratory. This tool's pathogenic predictio n is estimated to be correct 94% of the time (Jordan 2011). In summary, this var iant is likely pathogenic, though additional studies are required to fully estab lish its clinical significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		4	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000623804.5

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

Description

This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with aspartic acid at codon 153 of the TPM1 protein (p.His153Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID:¬†27532257).¬†ClinVar contains an entry for this variant (Variation ID: 43419). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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

Last Updated: Sep 29, 2024

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