NM_001018005.2(TPM1):c.797A>G (p.Lys266Arg) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 19, 2018
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:: RCV000154863.7

Allele description [Variation Report for NM_001018005.2(TPM1):c.797A>G (p.Lys266Arg)]

NM_001018005.2(TPM1):c.797A>G (p.Lys266Arg)

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.797A>G (p.Lys266Arg)

HGVS:

NC_000015.10:g.63064088A>G
NG_007557.1:g.26450A>G
NM_000366.6:c.797A>G
NM_001018004.2:c.772+1443A>G
NM_001018005.2:c.797A>GMANE SELECT
NM_001018006.2:c.772+1443A>G
NM_001018007.2:c.772+1443A>G
NM_001018008.2:c.664+1443A>G
NM_001018020.2:c.772+1443A>G
NM_001301244.2:c.797A>G
NM_001301289.2:c.664+1443A>G
NM_001330344.2:c.664+1443A>G
NM_001330346.2:c.689A>G
NM_001330351.2:c.664+1443A>G
NM_001365776.1:c.772+1443A>G
NM_001365777.1:c.772+1443A>G
NM_001365778.1:c.898+1443A>G
NM_001365779.1:c.797A>G
NM_001365780.1:c.664+1443A>G
NM_001365781.2:c.689A>G
NM_001365782.1:c.689A>G
NP_000357.3:p.Lys266Arg
NP_001018005.1:p.Lys266Arg
NP_001288173.1:p.Lys266Arg
NP_001317275.1:p.Lys230Arg
NP_001352708.1:p.Lys266Arg
NP_001352710.1:p.Lys230Arg
NP_001352711.1:p.Lys230Arg
LRG_387t1:c.797A>G
LRG_387:g.26450A>G
LRG_387p1:p.Lys266Arg
NC_000015.9:g.63356287A>G
NM_000366.5:c.797A>G
NM_001018005.1:c.797A>G

Protein change:

K230R

Links:

dbSNP: rs371934474

NCBI 1000 Genomes Browser:

rs371934474

Molecular consequence:

NM_001018004.2:c.772+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018006.2:c.772+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018007.2:c.772+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018008.2:c.664+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001018020.2:c.772+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001301289.2:c.664+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001330344.2:c.664+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001330351.2:c.664+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365776.1:c.772+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365777.1:c.772+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365778.1:c.898+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001365780.1:c.664+1443A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000366.6:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.689A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.689A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.689A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204545	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 17, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000920324	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 19, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22958901, 27532257 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204545

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 17, 2014)

germline

clinical testing

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

SCV000920324

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 19, 2018)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.

Bick AG, Flannick J, Ito K, Cheng S, Vasan RS, Parfenov MG, Herman DS, DePalma SR, Gupta N, Gabriel SB, Funke BH, Rehm HL, Benjamin EJ, Aragam J, Taylor HA Jr, Fox ER, Newton-Cheh C, Kathiresan S, O'Donnell CJ, Wilson JG, Altshuler DM, Hirschhorn JN, et al.

Am J Hum Genet. 2012 Sep 7;91(3):513-9. doi: 10.1016/j.ajhg.2012.07.017.

PubMed [citation]

PMID:: 22958901
PMCID:: PMC3511985

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204545.5

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

Description

The Lys266Arg variant in TPM1 has not been previously reported in any other fami lies with cardiomyopathy, but has been identified in 1/4406 African American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an imp act to the protein. Additional information is needed to fully assess the clinica l significance of this variant.

#	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		2	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920324.1

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

Description

Variant summary: TPM1 c.797A>G (p.Lys266Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 277096 control chromosomes, predominantly within the African subpopulation at a frequency of 0.00083 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPM1 causing Cardiomyopathy phenotype (7.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.797A>G has been reported in the literature in two individuals affected with Cardiomyopathy (Walsh 2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

#	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 20, 2024

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