NM_001267550.2(TTN):c.51782G>A (p.Arg17261Gln) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 23, 2024
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:: RCV000220238.6

Allele description [Variation Report for NM_001267550.2(TTN):c.51782G>A (p.Arg17261Gln)]

NM_001267550.2(TTN):c.51782G>A (p.Arg17261Gln)

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.51782G>A (p.Arg17261Gln)

Other names:

p.R15620Q:CGA>CAA

HGVS:

NC_000002.12:g.178609528C>T
NG_011618.3:g.226275G>A
NG_051363.1:g.91702C>T
NM_001256850.1:c.46859G>A
NM_001267550.2:c.51782G>AMANE SELECT
NM_003319.4:c.24587G>A
NM_133378.4:c.44078G>A
NM_133432.3:c.24962G>A
NM_133437.4:c.25163G>A
NP_001243779.1:p.Arg15620Gln
NP_001254479.2:p.Arg17261Gln
NP_003310.4:p.Arg8196Gln
NP_596869.4:p.Arg14693Gln
NP_597676.3:p.Arg8321Gln
NP_597681.4:p.Arg8388Gln
LRG_391:g.226275G>A
NC_000002.11:g.179474255C>T
Q8WZ42:p.Arg15620Gln

Protein change:

R14693Q

Links:

UniProtKB: Q8WZ42#VAR_040165; dbSNP: rs201825412

NCBI 1000 Genomes Browser:

rs201825412

Molecular consequence:

NM_001256850.1:c.46859G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.51782G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.24587G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.44078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.24962G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.25163G>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
SCV000272676	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005395201	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 23, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23396983, 30021846 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272676

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 20, 2015)

germline

clinical testing

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

SCV005395201

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 23, 2024)

germline

clinical testing

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

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	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

Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.

Lopes LR, Zekavati A, Syrris P, Hubank M, Giambartolomei C, Dalageorgou C, Jenkins S, McKenna W; Uk10k Consortium, Plagnol V, Elliott PM.

J Med Genet. 2013 Apr;50(4):228-39. doi: 10.1136/jmedgenet-2012-101270. Epub 2013 Feb 8.

PubMed [citation]

PMID:: 23396983
PMCID:: PMC3607113

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272676.3

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

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Arg14693Gln v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 14/66106 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201825412). Argin ine (Arg) at position 14693 is not conserved in evolutionarily distant species a nd 3 species (painted turtle, lizard, and frog) carry a glutamine (Gln) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide strong support for or against an i mpact to the protein. In summary, while the clinical significance of the p.Arg14 693Gln variant is uncertain, the present of the variant amino acid in multiple o ther species suggests that it is more likely to be benign.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005395201.1

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

Description

Variant summary: TTN c.44078G>A (p.Arg14693Gln) results in a conservative amino acid change located in the A-band (cardiodb.org) of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 246584 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.0001 vs 0.00039), allowing no conclusion about variant significance. c.44078G>A has been reported in the literature in at least an individual affected with hypertrophic cardiomyopathy (example: Lopes_2013) 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 publications have been ascertained in the context of this evaluation (PMID: 30021846, 23396983). ClinVar contains an entry for this variant (Variation ID: 202697). 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: Nov 18, 2024

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