NM_001267550.2(TTN):c.67348+1G>A AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 13, 2016
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:: RCV000414246.5

Allele description [Variation Report for NM_001267550.2(TTN):c.67348+1G>A]

NM_001267550.2(TTN):c.67348+1G>A

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.67348+1G>A

HGVS:

NC_000002.12:g.178579938C>T
NG_011618.3:g.255865G>A
NG_051363.1:g.62112C>T
NM_001256850.1:c.62425+1G>A
NM_001267550.2:c.67348+1G>AMANE SELECT
NM_003319.4:c.40153+1G>A
NM_133378.4:c.59644+1G>A
NM_133432.3:c.40528+1G>A
NM_133437.4:c.40729+1G>A
LRG_391t1:c.67348+1G>A
LRG_391:g.255865G>A
NC_000002.11:g.179444665C>T
NM_003319.4:c.40153+1G>A

Links:

dbSNP: rs758279518

NCBI 1000 Genomes Browser:

rs758279518

Molecular consequence:

NM_001256850.1:c.62425+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001267550.2:c.67348+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_003319.4:c.40153+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133378.4:c.59644+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133432.3:c.40528+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133437.4:c.40729+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Functional consequence:

effect on RNA splicing [Variation Ontology: 0362]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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At.65910 AND (alive[prop]) (0)
Gene
HS6ST3 [Tauraco erythrolophus]
HS6ST3 [Tauraco erythrolophus]
Gene ID:104374176

Gene
LOC107622455 [Arachis ipaensis]
LOC107622455 [Arachis ipaensis]
Gene ID:107622455

Gene
GCNT1 [Tauraco erythrolophus]
GCNT1 [Tauraco erythrolophus]
Gene ID:104379951

Gene
hs3st2 [Larimichthys crocea]
hs3st2 [Larimichthys crocea]
Gene ID:104918711

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000331945	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Jul 1, 2015)	germline	clinical testing	Citation Link,
SCV000491396	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Jan 13, 2016)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000331945

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Likely pathogenic
(Jul 1, 2015)

germline

clinical testing

Citation Link,

SCV000491396

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Jan 13, 2016)

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	unknown	1	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

Details of each submission

From Eurofins Ntd Llc (ga), SCV000331945.4

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000491396.1

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

Description

Although the c.62425+1 G>A variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, it destroys the canonical splice donor site in intron 268 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, the c.62425+1 G>A variant is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Multiple other downstream splice site variants in the TTN gene have been reported in HGMD in association with DCM (Stenson et al., 2014), including another variant affecting the same donor site (c.62425+5 G>A). Furthermore, the c.62425+1 G>A variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.62425+1 G>A in the TTN gene is interpreted as a pathogenic variant.

#	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: Sep 29, 2024

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