NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 17, 2024
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:: RCV000474684.14

Allele description [Variation Report for NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)]

NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)

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.523G>A (p.Asp175Asn)

Other names:

p.D175N:GAC>AAC

HGVS:

NC_000015.10:g.63060899G>A
NG_007557.1:g.23261G>A
NM_000366.6:c.523G>A
NM_001018004.2:c.523G>A
NM_001018005.2:c.523G>AMANE SELECT
NM_001018006.2:c.523G>A
NM_001018007.2:c.523G>A
NM_001018008.2:c.415G>A
NM_001018020.2:c.523G>A
NM_001301244.2:c.523G>A
NM_001301289.2:c.415G>A
NM_001330344.2:c.415G>A
NM_001330346.2:c.415G>A
NM_001330351.2:c.415G>A
NM_001365776.1:c.523G>A
NM_001365777.1:c.523G>A
NM_001365778.1:c.649G>A
NM_001365779.1:c.523G>A
NM_001365780.1:c.415G>A
NM_001365781.2:c.415G>A
NM_001365782.1:c.415G>A
NP_000357.3:p.Asp175Asn
NP_001018004.1:p.Asp175Asn
NP_001018005.1:p.Asp175Asn
NP_001018006.1:p.Asp175Asn
NP_001018007.1:p.Asp175Asn
NP_001018008.1:p.Asp139Asn
NP_001018020.1:p.Asp175Asn
NP_001288173.1:p.Asp175Asn
NP_001288218.1:p.Asp139Asn
NP_001317273.1:p.Asp139Asn
NP_001317275.1:p.Asp139Asn
NP_001317280.1:p.Asp139Asn
NP_001352705.1:p.Asp175Asn
NP_001352706.1:p.Asp175Asn
NP_001352707.1:p.Asp217Asn
NP_001352708.1:p.Asp175Asn
NP_001352709.1:p.Asp139Asn
NP_001352710.1:p.Asp139Asn
NP_001352711.1:p.Asp139Asn
LRG_387t1:c.523G>A
LRG_387:g.23261G>A
LRG_387p1:p.Asp175Asn
NC_000015.9:g.63353098G>A
NM_000366.5:c.523G>A
NM_001018005.1:c.523G>A
NM_001018006.1:c.523G>A
P09493:p.Asp175Asn
c.523G>A
p.(Asp175Asn)

Protein change:

D139N; ASP175ASN

Links:

Leiden Muscular Dystrophy (TPM1): TPM1_00009; UniProtKB: P09493#VAR_007601; OMIM: 191010.0002; dbSNP: rs104894503

NCBI 1000 Genomes Browser:

rs104894503

Molecular consequence:

NM_000366.6:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018004.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018005.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018006.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018007.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018008.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001018020.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301244.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301289.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330344.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330346.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330351.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365776.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365777.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365778.1:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365779.1:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365780.1:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365781.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365782.1:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

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
SCV000059992	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (May 3, 2016)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 9440709, 7729014, 16014439, 14734051, 12473556, 8523464, 8205619, 16504640, 9060904, 21295541, 21320446, 21376702, 22187526, 22789852, 22794249, 22462493, 22155441, 10400910, 24033266
SCV000547697	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7729014, 8205619, 9060904, 22462493, 25548289, 9245729, 10400910, 10900175, 22155441, 28492532
SCV000747373	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004812546	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7729014, 9440709, 9822100, 10400910, 22462493, 25741868

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	15	10	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cine MR imaging of myocardial contractile impairment in patients with hypertrophic cardiomyopathy attributable to Asp175Asn mutation in the alpha-tropomyosin gene.

Sipola P, Lauerma K, Jääskeläinen P, Laakso M, Peuhkurinen K, Manninen H, Aronen HJ, Kuusisto J.

Radiology. 2005 Sep;236(3):815-24. Epub 2005 Jul 12.

PubMed [citation]

PMID:: 16014439

Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene.

Hedman A, Hartikainen J, Vanninen E, Laitinen T, Jääskeläinen P, Laakso M, Peuhkurinen K, Kuusisto J.

J Mol Cell Cardiol. 2004 Jan;36(1):91-9. Erratum in: J Mol Cell Cardiol. 2004 Apr;36(4):607-8.

PubMed [citation]

PMID:: 14734051

See all PubMed Citations (25)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059992.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	PubMed (19)

Description

The p.Asp175Asn variant in TPM1 has been reported in multiple individuals with H CM, segregated with disease in more than 15 families, and occurred de novo in at least 1 individual (Thierfelder 1994, Nakajima-Taniguchi 1995, Watkins 1995, Co viello 1997, Van Driest 2002, Hedman 2004, Sipola 2005, Poutanen 2006, Jaaskelai nen 2013). It was also absent from large population studies. Additionally, funct ional studies support a pathogenic role for this variant (Bottinelli 1998, Muthu chamy 1999, Mathur 2011, Bai 2011, Borovikov 2011, Wang 2011, Li 2012, Ly 2012, Rysev 2012). In summary, the p.Asp175Asn variant meets our criteria to be classi fied as pathogenic for HCM in an autosomal dominant manner based on segregation studies and functional evidence.

#	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		15	not provided	10	not provided

From Invitae, SCV000547697.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 175 of the TPM1 protein (p.Asp175Asn). This variant is present in population databases (rs104894503, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) in many families, and is a common cause of HCM in Finland (PMID: 7729014, 8205619, 9060904, 22462493, 25548289). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12456). 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. Experimental studies have shown that this missense change affects TPM1 function (PMID: 9245729, 10400910, 10900175, 22155441). For these reasons, this variant has been classified as Pathogenic.

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV000747373.1

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

From Molecular Genetics, Royal Melbourne Hospital, SCV004812546.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change in TPM1 is predicted to replace aspartic acid with asparagine at codon 175, p.(Asp175Asn). The aspartic acid residue is highly conserved (100 vertebrates, Multiz alignments), and is located in the coiled-coil domain. There is a small physicochemical difference between aspartic acid and asparagine. TPM1, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (8/64,018 alleles) in the Finnish population, while the highest population frequency in a non-bottlenecked population is 0.0003% (4/1,180,052 alleles) in the European (non-Finnish) population. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy and is the reported founder mutation in the Finnish population and segregates with cardiomyopathy in multiple unrelated families (PMID: 9822100, 22462493). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with hypertrophic cardiomyopathy (PMID: 7729014). An in vitro functional assay in heart muscle fibres and a transgenic mouse model expressing this variant in the heart showed an increase in calcium ion (Ca2+) sensitivity (PMID: 9440709, 10400910). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.785). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4, PM2_Supporting, PS2_Supporting, PP2, PP3, PS3_Moderate.

#	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: Apr 15, 2024

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