NM_001267550.2(TTN):c.30511+3G>A AND not specified

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jun 6, 2018
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:: RCV000445119.10

Allele description [Variation Report for NM_001267550.2(TTN):c.30511+3G>A]

NM_001267550.2(TTN):c.30511+3G>A

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.30511+3G>A

HGVS:

NC_000002.12:g.178702165C>T
NG_011618.3:g.133638G>A
NM_001256850.1:c.29560+3G>A
NM_001267550.2:c.30511+3G>AMANE SELECT
NM_003319.4:c.13282+35917G>A
NM_133378.4:c.26779+3G>A
NM_133432.3:c.13657+35917G>A
NM_133437.4:c.13858+35917G>A
LRG_391:g.133638G>A
NC_000002.11:g.179566892C>T

Links:

dbSNP: rs563582627

NCBI 1000 Genomes Browser:

rs563582627

Molecular consequence:

NM_001256850.1:c.29560+3G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001267550.2:c.30511+3G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_003319.4:c.13282+35917G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_133378.4:c.26779+3G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_133432.3:c.13657+35917G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_133437.4:c.13858+35917G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV000515111	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Mar 31, 2015)	germline	clinical testing	Citation Link,
SCV000731280	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 6, 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

SCV000515111

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Benign
(Mar 31, 2015)

germline

clinical testing

Citation Link,

SCV000731280

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jun 6, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From GeneDx, SCV000515111.4

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731280.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

Variant classified as Uncertain Significance - Favor Benign. The c.26779+3G>A va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.02% (7/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5 63582627). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing; however, this information is not predictive en ough to determine pathogenicity. In summary, while the clinical significance of the c.26779+3G>A variant is uncertain, its frequency suggests that it is more l ikely to be benign. ACMG/AMP Criteria applied: BS1; PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

Last Updated: Feb 1, 2025

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