NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Nov 30, 2022
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:: RCV000024580.11

Allele description [Variation Report for NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)]

NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)

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.688G>A (p.Asp230Asn)

Other names:

p.D230N:GAC>AAC

HGVS:

NC_000015.10:g.63062263G>A
NG_007557.1:g.24625G>A
NM_000366.6:c.688G>A
NM_001018004.1:c.688G>A
NM_001018004.2:c.688G>A
NM_001018005.2:c.688G>AMANE SELECT
NM_001018006.2:c.688G>A
NM_001018007.2:c.688G>A
NM_001018008.2:c.580G>A
NM_001018020.2:c.688G>A
NM_001301244.2:c.688G>A
NM_001301289.2:c.580G>A
NM_001330344.2:c.580G>A
NM_001330346.2:c.580G>A
NM_001330351.2:c.580G>A
NM_001365776.1:c.688G>A
NM_001365777.1:c.688G>A
NM_001365778.1:c.814G>A
NM_001365779.1:c.688G>A
NM_001365780.1:c.580G>A
NM_001365781.2:c.580G>A
NM_001365782.1:c.580G>A
NP_000357.3:p.Asp230Asn
NP_001018004.1:p.Asp230Asn
NP_001018005.1:p.Asp230Asn
NP_001018006.1:p.Asp230Asn
NP_001018007.1:p.Asp230Asn
NP_001018008.1:p.Asp194Asn
NP_001018020.1:p.Asp230Asn
NP_001288173.1:p.Asp230Asn
NP_001288218.1:p.Asp194Asn
NP_001317273.1:p.Asp194Asn
NP_001317275.1:p.Asp194Asn
NP_001317280.1:p.Asp194Asn
NP_001352705.1:p.Asp230Asn
NP_001352706.1:p.Asp230Asn
NP_001352707.1:p.Asp272Asn
NP_001352708.1:p.Asp230Asn
NP_001352709.1:p.Asp194Asn
NP_001352710.1:p.Asp194Asn
NP_001352711.1:p.Asp194Asn
LRG_387t1:c.688G>A
LRG_387:g.24625G>A
LRG_387p1:p.Asp230Asn
NC_000015.9:g.63354462G>A
NM_000366.5:c.688G>A
NM_001018005.1:c.688G>A
c.688G>A
p.(Asp230Asn)

Protein change:

D194N

Links:

Leiden Muscular Dystrophy (TPM1): TPM1_00015; dbSNP: rs199476317

NCBI 1000 Genomes Browser:

rs199476317

Molecular consequence:

NM_000366.6:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018008.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301289.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330344.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330351.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365780.1:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.580G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045889	Leiden Muscular Dystrophy (TPM1)	no classification provided	not provided	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV000209327	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 30, 2022)	germline	clinical testing	Citation Link,
SCV000280541	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Nov 7, 2014)	germline	clinical testing
SCV000340451	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Mar 11, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005196871	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy.

Lakdawala NK, Dellefave L, Redwood CS, Sparks E, Cirino AL, Depalma S, Colan SD, Funke B, Zimmerman RS, Robinson P, Watkins H, Seidman CE, Seidman JG, McNally EM, Ho CY.

J Am Coll Cardiol. 2010 Jan 26;55(4):320-9. doi: 10.1016/j.jacc.2009.11.017.

PubMed [citation]

PMID:: 20117437
PMCID:: PMC3000630

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 Leiden Muscular Dystrophy (TPM1), SCV000045889.1

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

#	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		not provided	not provided	not provided	not provided

From GeneDx, SCV000209327.14

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

Description

Reported in association with dilated cardiomyopathy (Lakdawala et al., 2010; Pugh et al., 2014; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant significantly impairs sarcomere function compared to wild-type TPM1 protein (Lakdawala et al., 2010; Memo et al., 2013); This variant is associated with the following publications: (PMID: 23539503, 25548289, 23836688, 25202278, 25241052, 25525159, 21310275, 28166811, 23281406, 25179549, 21483645, 24503780, 27872154, 28600229, 31216405, 31983221, 20117437, 27532257, 34935411)

#	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		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280541.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp230Asn (c.688 G>A) in TPM1 The variant has been seen in at least 2 unrelated cases of familial DCM with strong segregation data (not including our patient's family). Lakdawala et al (2010) observed the variant in two Caucasian families with DCM. Ten affected members of one family and 6 affected members of there other family carried the variant. The authors report that 21 of 25 unaffected adult family members did not have the variant. The combined LOD score was 5.22. There was marked intrafamilial variability with some family members diagnosed in the first year of life and others diagnosed in mid-adulthood. The same group later reported on early phenotypes in DCM including individuals with p.Asp230Asn (Lakdawala et al 2012). Presumably these were the same families as their prior report. This is a non-conservative amino acid substitution. The aspartate at codon 230 is conserved across species. PolyPhen predicts the variant to be possibly damaging. Lakdawala et al (2010) assessed the impact of the variant using an in vitro reconstituted sarcomere complex. They found inhibited sarcomere function with reduced calcium sensitivity, maximum activation and calcium affinity. A nearby variant has been reported in association with DCM, p.Ala239Thr (Stenson et al 2009). In total the variants has not been seen in at least 7000 published controls and publicly available general population samples. Lakdawala et al (2010) did not observe the variant in >500 Caucasian individuals. There is no variation at codon 230 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 28th, 2012). The variant is not listed in 1000 genomes (as of October 28th, 2012). It is listed in dbSNP, pointing to an online database for TPM1 variants that cites Lakdawala et al (2010).

#	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		3	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000340451.4

#	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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005196871.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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