NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Feb 24, 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:: RCV000159366.14

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]

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
SCV000209312	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 24, 2023)	germline	clinical testing	Citation Link,
SCV001762138	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001922946	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001929241	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001956834	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001966578	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

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	1	not provided	clinical testing

Citations

PubMed

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 GeneDx, SCV000209312.14

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Several published functional studies have shown the deleterious effects of p.(D175N) (Muthuchamy et al., 1999; Mathur et al., 2011; Ly et al., 2012; Sewanan et al., 2016), including an in vitro study performed by Bottinelli et al., 1998, that showed that p.(D175N) results in increased calcium sensitivity; This variant is associated with the following publications: (PMID: 32217077, 15000344, 8523464, 16504640, 9822100, 12473556, 16014439, 27833562, 7729014, 31270709, 30775854, 22462493, 22155441, 21295541, 21376702, 22789852, 9245729, 10900175, 22794249, 21320446, 22187526, 25241052, 10400910, 23283745, 8205619, 21310275, 27878731, 27532257, 28166811, 29915098, 29760186, 8774330, 9060904, 11606294, 7898523, 30165862, 30923661, 31643006, 14734051, 9440709, 33906374, 33673806, 35653365, 28193612)

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001762138.1

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001922946.1

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

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001929241.1

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

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956834.1

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

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001966578.1

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

#	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: May 7, 2024

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