NM_001267550.2(TTN):c.50858-3C>T AND not specified

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Feb 16, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV000225702.15

Allele description [Variation Report for NM_001267550.2(TTN):c.50858-3C>T]

NM_001267550.2(TTN):c.50858-3C>T

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.50858-3C>T

HGVS:

NC_000002.12:g.178611274G>A
NG_011618.3:g.224529C>T
NG_051363.1:g.93448G>A
NM_001256850.1:c.45935-3C>T
NM_001267550.2:c.50858-3C>TMANE SELECT
NM_003319.4:c.23663-3C>T
NM_133378.4:c.43154-3C>T
NM_133432.3:c.24038-3C>T
NM_133437.4:c.24239-3C>T
LRG_391t1:c.50858-3C>T
LRG_391:g.224529C>T
NC_000002.11:g.179476001G>A
NM_001267550.1:c.50858-3C>T
NM_003319.4:c.23663-3C>T
NM_133379.3:c.*134311C>T

Links:

dbSNP: rs587782987

NCBI 1000 Genomes Browser:

rs587782987

Molecular consequence:

NM_001256850.1:c.45935-3C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001267550.2:c.50858-3C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_003319.4:c.23663-3C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_133378.4:c.43154-3C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_133432.3:c.24038-3C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_133437.4:c.24239-3C>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000236652	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Mar 15, 2018)	germline	clinical testing	Citation Link,
SCV001623315	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 26, 2024)	germline	clinical testing	Citation Link,
SCV006108698	Laboratory of Genetics, Children's Clinical University Hospital Latvia	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Feb 16, 2025)	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

SCV000236652

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Mar 15, 2018)

germline

clinical testing

Citation Link,

SCV001623315

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 26, 2024)

germline

clinical testing

Citation Link,

SCV006108698

Laboratory of Genetics, Children's Clinical University Hospital Latvia

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Feb 16, 2025)

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
not provided	germline	yes	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 GeneDx, SCV000236652.9

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623315.2

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

Description

Variant summary: TTN c.43154-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 246042 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00039). To our knowledge, no occurrence of c.43154-3C>T in individuals affected with TTN-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 155849). Based on the evidence outlined above, the variant was classified as VUS.

#	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 Laboratory of Genetics, Children's Clinical University Hospital Latvia, SCV006108698.1

#	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: Nov 2, 2025

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