NM_001267550.2(TTN):c.70492G>A (p.Gly23498Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 19, 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:: RCV000040556.7

Allele description [Variation Report for NM_001267550.2(TTN):c.70492G>A (p.Gly23498Ser)]

NM_001267550.2(TTN):c.70492G>A (p.Gly23498Ser)

Genes:

LOC126806422:BRD4-independent group 4 enhancer GRCh37_chr2:179440205-179441404 [Gene]
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.70492G>A (p.Gly23498Ser)

Other names:

p.G20930S:GGC>AGC

HGVS:

NC_000002.12:g.178575640C>T
NG_011618.3:g.260163G>A
NG_051363.1:g.57814C>T
NM_001256850.1:c.65569G>A
NM_001267550.2:c.70492G>AMANE SELECT
NM_003319.4:c.43297G>A
NM_133378.4:c.62788G>A
NM_133432.3:c.43672G>A
NM_133437.4:c.43873G>A
NP_001243779.1:p.Gly21857Ser
NP_001254479.2:p.Gly23498Ser
NP_003310.4:p.Gly14433Ser
NP_596869.4:p.Gly20930Ser
NP_597676.3:p.Gly14558Ser
NP_597681.4:p.Gly14625Ser
LRG_391:g.260163G>A
NC_000002.11:g.179440367C>T
NM_003319.4:c.43297G>A
c.62788G>A

Protein change:

G14433S

Links:

dbSNP: rs370771532

NCBI 1000 Genomes Browser:

rs370771532

Molecular consequence:

NM_001256850.1:c.65569G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.70492G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.43297G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.62788G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.43672G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.43873G>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
SCV000064247	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Dec 3, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004020325	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064247

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Dec 3, 2013)

germline

clinical testing

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

SCV004020325

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 19, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	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

A 14-year-old in heart failure with multiple cardiomyopathy variants illustrates a role for signal-to-noise analysis in gene test re-interpretation.

Connell PS, Jeewa A, Kearney DL, Tunuguntla H, Denfield SW, Allen HD, Landstrom AP.

Clin Case Rep. 2019 Jan;7(1):211-217. doi: 10.1002/ccr3.1920.

PubMed [citation]

PMID:: 30656044
PMCID:: PMC6332775

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064247.6

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

Description

The Gly20930Ser variant in TTN has now been identified by our laboratory in 1 As hkenazi Jewish adult with HCM and 1 Caucasian adult with DCM. This variant has a lso been identified in 1/8264 European American and 1/3864 African American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) . Computational analyses (biochemical amino acid properties, conservation, Align GVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impac t to the protein. Additional information is needed to fully assess the clinical significance of the Gly20930Ser 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		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020325.1

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

Description

Variant summary: TTN c.62788G>A (p.Gly20930Ser) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 248498 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00023 vs 0.00039), allowing no conclusion about variant significance. c.62788G>A has been reported in the literature in an individual affected with Cardiomyopathy without evidence for causality (Connell_2019). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30656044). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either VUS (n=4) or benign (n=1)/likely benign (n=1). 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: Jan 13, 2025

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