NM_001267550.2(TTN):c.26762-10_26762-9insTTGTTTTGTA AND not specified

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Aug 14, 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:: RCV000480310.10

Allele description [Variation Report for NM_001267550.2(TTN):c.26762-10_26762-9insTTGTTTTGTA]

NM_001267550.2(TTN):c.26762-10_26762-9insTTGTTTTGTA

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.26762-10_26762-9insTTGTTTTGTA

HGVS:

NC_000002.12:g.178713385_178713386insTACAAAACAA
NG_011618.3:g.122421_122422insTTTGTATTGT
NM_001256850.1:c.25811-10_25811-9insTTGTTTTGTA
NM_001267550.2:c.26762-10_26762-9insTTGTTTTGTAMANE SELECT
NM_003319.4:c.13282+24700_13282+24701insTTGTTTTGTA
NM_133378.4:c.23030-10_23030-9insTTGTTTTGTA
NM_133432.3:c.13657+24700_13657+24701insTTGTTTTGTA
NM_133437.4:c.13858+24700_13858+24701insTTGTTTTGTA
LRG_391:g.122421_122422insTTTGTATTGT
NC_000002.11:g.179578108_179578109insACAATACAAA
NC_000002.11:g.179578112_179578113insTACAAAACAA
NM_001256850.1:c.25811-10_25811-9insTTTGTATTGT
NM_001267550.2:c.26762-10_26762-9insTTTGTATTGTMANE SELECT
NM_133378.4:c.23030-10_23030-9insTTTGTATTGT

Links:

dbSNP: rs1553893826

NCBI 1000 Genomes Browser:

rs1553893826

Molecular consequence:

NM_001256850.1:c.25811-10_25811-9insTTGTTTTGTA - intron variant - [Sequence Ontology: SO:0001627]
NM_001267550.2:c.26762-10_26762-9insTTGTTTTGTA - intron variant - [Sequence Ontology: SO:0001627]
NM_003319.4:c.13282+24700_13282+24701insTTGTTTTGTA - intron variant - [Sequence Ontology: SO:0001627]
NM_133378.4:c.23030-10_23030-9insTTGTTTTGTA - intron variant - [Sequence Ontology: SO:0001627]
NM_133432.3:c.13657+24700_13657+24701insTTGTTTTGTA - intron variant - [Sequence Ontology: SO:0001627]
NM_133437.4:c.13858+24700_13858+24701insTTGTTTTGTA - 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
SCV000568172	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Dec 28, 2017)	germline	clinical testing	Citation Link,
SCV000597667	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Dec 23, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004039494	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Aug 14, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568172

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Dec 28, 2017)

germline

clinical testing

Citation Link,

SCV000597667

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Dec 23, 2016)

germline

clinical testing

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

SCV004039494

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Aug 14, 2023)

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
not provided	germline	no	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, SCV000568172.4

#	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 Genetic Services Laboratory, University of Chicago, SCV000597667.1

#	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	no	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, SCV004039494.1

#	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.23030-10_23030-9insTTTGTATTGT results in the insertion of 10 nucleotides at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: four predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00037 in 149680 control chromosomes (i.e., 55 heterozygotes), predominantly at a frequency of 0.00053 within the Non-Finnish European subpopulation in the gnomAD database (v3.1.2). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.23030-10_23030-9insTTTGTATTGT in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; three submitters classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

#	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: Mar 5, 2024

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