NM_001267550.2(TTN):c.1489G>T (p.Glu497Ter) AND Primary dilated cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 25, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004017821.1

Allele description [Variation Report for NM_001267550.2(TTN):c.1489G>T (p.Glu497Ter)]

NM_001267550.2(TTN):c.1489G>T (p.Glu497Ter)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.1489G>T (p.Glu497Ter)

HGVS:

NC_000002.12:g.178793451C>A
NG_011618.3:g.42352G>T
NM_001256850.1:c.1489G>T
NM_001267550.2:c.1489G>TMANE SELECT
NM_003319.4:c.1489G>T
NM_133378.4:c.1489G>T
NM_133379.5:c.1489G>T
NM_133432.3:c.1489G>T
NM_133437.4:c.1489G>T
NP_001243779.1:p.Glu497Ter
NP_001254479.2:p.Glu497Ter
NP_003310.4:p.Glu497Ter
NP_596869.4:p.Glu497Ter
NP_596870.2:p.Glu497Ter
NP_597676.3:p.Glu497Ter
NP_597681.4:p.Glu497Ter
LRG_391:g.42352G>T
NC_000002.11:g.179658178C>A

Protein change:

E497*

Links:

dbSNP: rs1185562018

NCBI 1000 Genomes Browser:

rs1185562018

Molecular consequence:

NM_001256850.1:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133379.5:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.1489G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848230	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 25, 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

SCV004848230

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Jul 25, 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	unknown	not provided	not provided	not provided	not provided	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848230.1

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

Description

The p.Glu497X variant in TTN has not been previously reported in individuals with DCM and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 497, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Glu497X variant is located in Z-band in the highly expressed exon 9. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu497X variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2.

#	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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