NM_001267550.2(TTN):c.104936G>C (p.Gly34979Ala) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 2, 2023
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:: RCV000825259.6

Allele description [Variation Report for NM_001267550.2(TTN):c.104936G>C (p.Gly34979Ala)]

NM_001267550.2(TTN):c.104936G>C (p.Gly34979Ala)

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.104936G>C (p.Gly34979Ala)

HGVS:

NC_000002.12:g.178531679C>G
NG_011618.3:g.304124G>C
NG_051363.1:g.13853C>G
NM_001256850.1:c.100013G>C
NM_001267550.2:c.104936G>CMANE SELECT
NM_003319.4:c.77741G>C
NM_133378.4:c.97232G>C
NM_133432.3:c.78116G>C
NM_133437.4:c.78317G>C
NP_001243779.1:p.Gly33338Ala
NP_001254479.2:p.Gly34979Ala
NP_003310.4:p.Gly25914Ala
NP_596869.4:p.Gly32411Ala
NP_597676.3:p.Gly26039Ala
NP_597681.4:p.Gly26106Ala
LRG_391:g.304124G>C
NC_000002.11:g.179396406C>G
p.Gly32411Ala

Protein change:

G25914A

Links:

dbSNP: rs376634193

NCBI 1000 Genomes Browser:

rs376634193

Molecular consequence:

NM_001256850.1:c.100013G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.104936G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.77741G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.97232G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.78116G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.78317G>C - 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
SCV000966547	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jan 2, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004121842	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 2, 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

SCV000966547

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jan 2, 2019)

germline

clinical testing

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

SCV004121842

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 2, 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	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

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes TJW, Felkin LE, Ahmad M, Theotokis PI, Edwards E, Ing AY, Thomson KL, Chan LLH, Sim D, Baksi AJ, Pantazis A, Roberts AM, Watkins H, et al.

Circulation. 2020 Feb 4;141(5):387-398. doi: 10.1161/CIRCULATIONAHA.119.037661. Epub 2020 Jan 27.

PubMed [citation]

PMID:: 31983221
PMCID:: PMC7004454

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966547.1

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

Description

The p.Gly32411Ala variant in TTN is classified as likely benign because it has b een identified in 0.01% (18/128300) of European chromosomes by gnomAD (http://gn omad.broadinstitute.org) and was identified in trans with a likely pathogenic va riant. ACMG/AMP Criteria applied: BS1_Supporting, BP2.

#	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, SCV004121842.1

#	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.97232G>C (p.Gly32411Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 249104 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8e-05 vs 0.00039), allowing no conclusion about variant significance. c.97232G>C has been reported in the literature in an individual from a Dilated Cardiomyopathy cohort (Mazzarotto_2020). 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 publication has been ascertained in the context of this evaluation (PMID: 31983221). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=4) and likely benign (n=3). 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: Apr 15, 2024

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