NM_001267550.2(TTN):c.95083G>A (p.Gly31695Arg) AND not specified

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 28, 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:: RCV000040818.10

Allele description [Variation Report for NM_001267550.2(TTN):c.95083G>A (p.Gly31695Arg)]

NM_001267550.2(TTN):c.95083G>A (p.Gly31695Arg)

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.95083G>A (p.Gly31695Arg)

Other names:

p.G30054R:GGG>AGG

HGVS:

NC_000002.12:g.178546248C>T
NG_011618.3:g.289555G>A
NG_051363.1:g.28422C>T
NM_001256850.1:c.90160G>A
NM_001267550.2:c.95083G>AMANE SELECT
NM_003319.4:c.67888G>A
NM_133378.4:c.87379G>A
NM_133432.3:c.68263G>A
NM_133437.4:c.68464G>A
NP_001243779.1:p.Gly30054Arg
NP_001254479.2:p.Gly31695Arg
NP_003310.4:p.Gly22630Arg
NP_596869.4:p.Gly29127Arg
NP_597676.3:p.Gly22755Arg
NP_597681.4:p.Gly22822Arg
LRG_391t1:c.95083G>A
LRG_391:g.289555G>A
NC_000002.11:g.179410975C>T
NM_001267550.1:c.95083G>A
c.87379G>A

Protein change:

G22630R

Links:

dbSNP: rs376403373

NCBI 1000 Genomes Browser:

rs376403373

Molecular consequence:

NM_001256850.1:c.90160G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.95083G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.67888G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.87379G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.68263G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.68464G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000064509	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Apr 30, 2012)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000237801	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 31, 2014)	germline	clinical testing	Citation Link,
SCV000616184	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Oct 28, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23418287, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064509

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Apr 30, 2012)

germline

clinical testing

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

SCV000237801

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 31, 2014)

germline

clinical testing

Citation Link,

SCV000616184

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Oct 28, 2016)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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	not provided	1	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

Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy.

Norton N, Li D, Rampersaud E, Morales A, Martin ER, Zuchner S, Guo S, Gonzalez M, Hedges DJ, Robertson PD, Krumm N, Nickerson DA, Hershberger RE; National Heart, Lung, and Blood Institute GO Exome Sequencing Project and the Exome Sequencing Project Family Studies Project Team.

Circ Cardiovasc Genet. 2013 Apr;6(2):144-53. doi: 10.1161/CIRCGENETICS.111.000062. Epub 2013 Feb 15.

PubMed [citation]

PMID:: 23418287
PMCID:: PMC3815606

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064509.6

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

Description

The Gly29127Arg variant (TTN) has not previously been reported in the literature nor previously identified by our laboratory. This variant has been identified i n 0.06% (2/3250) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/); however, thi s frequency is too low to confidently rule out a disease causing role. Computati onal analyses (biochemical amino acid properties, conservation, and SIFT) sugges t that this variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, additional information is n eeded to fully assess the clinical significance of the Gly29127Arg variant.

#	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		1	not provided	1	not provided

From GeneDx, SCV000237801.6

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

Description

Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s).

#	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 Athena Diagnostics, SCV000616184.1

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

#	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: Jul 29, 2024

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