NM_001267550.2(TTN):c.68981C>T (p.Thr22994Ile) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 15, 2023
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:: RCV000601528.3

Allele description [Variation Report for NM_001267550.2(TTN):c.68981C>T (p.Thr22994Ile)]

NM_001267550.2(TTN):c.68981C>T (p.Thr22994Ile)

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.68981C>T (p.Thr22994Ile)

HGVS:

NC_000002.12:g.178577354G>A
NG_011618.3:g.258449C>T
NG_051363.1:g.59528G>A
NM_001256850.1:c.64058C>T
NM_001267550.2:c.68981C>TMANE SELECT
NM_003319.4:c.41786C>T
NM_133378.4:c.61277C>T
NM_133432.3:c.42161C>T
NM_133437.4:c.42362C>T
NP_001243779.1:p.Thr21353Ile
NP_001254479.2:p.Thr22994Ile
NP_003310.4:p.Thr13929Ile
NP_596869.4:p.Thr20426Ile
NP_597676.3:p.Thr14054Ile
NP_597681.4:p.Thr14121Ile
LRG_391:g.258449C>T
NC_000002.11:g.179442081G>A
NM_003319.4:c.41786C>T

Protein change:

T13929I

Links:

dbSNP: rs183056142

NCBI 1000 Genomes Browser:

rs183056142

Molecular consequence:

NM_001256850.1:c.64058C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.68981C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.41786C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.61277C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.42161C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.42362C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000730405	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (May 16, 2017)	germline	clinical testing	Citation Link,
SCV003934126	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000730405

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(May 16, 2017)

germline

clinical testing

Citation Link,

SCV003934126

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 15, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting.

Christiansen SL, Hertz CL, Ferrero-Miliani L, Dahl M, Weeke PE, LuCamp, Ottesen GL, Frank-Hansen R, Bundgaard H, Morling N.

Eur J Hum Genet. 2016 Dec;24(12):1797-1802. doi: 10.1038/ejhg.2016.118. Epub 2016 Sep 21.

PubMed [citation]

PMID:: 27650965
PMCID:: PMC5117921

Details of each submission

From GeneDx, SCV000730405.1

#	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, SCV003934126.1

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

Description

Variant summary: TTN c.61277C>T (p.Thr20426Ile) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248534 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.8e-05 vs 0.00039), allowing no conclusion about variant significance. c.61277C>T has been reported in the literature in a compound heterozygous individual with sudden unexplained death (Christiansen_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27650965). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance (n=2), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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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