NM_001267550.2(TTN):c.74372C>T (p.Thr24791Ile) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 7, 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:: RCV001811865.14

Allele description [Variation Report for NM_001267550.2(TTN):c.74372C>T (p.Thr24791Ile)]

NM_001267550.2(TTN):c.74372C>T (p.Thr24791Ile)

Genes:

TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.74372C>T (p.Thr24791Ile)

HGVS:

NC_000002.12:g.178571760G>A
NG_011618.3:g.264043C>T
NG_051363.1:g.53934G>A
NM_001256850.1:c.69449C>T
NM_001267550.2:c.74372C>TMANE SELECT
NM_003319.4:c.47177C>T
NM_133378.4:c.66668C>T
NM_133432.3:c.47552C>T
NM_133437.4:c.47753C>T
NP_001243779.1:p.Thr23150Ile
NP_001254479.2:p.Thr24791Ile
NP_003310.4:p.Thr15726Ile
NP_596869.4:p.Thr22223Ile
NP_597676.3:p.Thr15851Ile
NP_597681.4:p.Thr15918Ile
LRG_391:g.264043C>T
NC_000002.11:g.179436487G>A
NM_001267550.1:c.74372C>T

Protein change:

T15726I

Links:

dbSNP: rs1055906361

NCBI 1000 Genomes Browser:

rs1055906361

Molecular consequence:

NM_001256850.1:c.69449C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.74372C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.47177C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.66668C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.47552C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.47753C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002048479	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Jul 23, 2021)	germline	clinical testing	Citation Link,
SCV005396099	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 7, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002048479

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Jul 23, 2021)

germline

clinical testing

Citation Link,

SCV005396099

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 7, 2024)

germline

clinical testing

Citation Link

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048479.1

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

Description

The TTN c.66668C>T; p.Thr22223Ile variant (rs1055906361) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Thr22223Ile variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739.

#	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 GeneDx, SCV005396099.1

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge

#	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: Nov 24, 2024

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