NM_001267550.2(TTN):c.107089G>C (p.Glu35697Gln) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 22, 2022
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:: RCV000220851.11

Allele description [Variation Report for NM_001267550.2(TTN):c.107089G>C (p.Glu35697Gln)]

NM_001267550.2(TTN):c.107089G>C (p.Glu35697Gln)

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.107089G>C (p.Glu35697Gln)

HGVS:

NC_000002.12:g.178528662C>G
NG_011618.3:g.307141G>C
NG_051363.1:g.10836C>G
NM_001256850.1:c.102166G>C
NM_001267550.2:c.107089G>CMANE SELECT
NM_003319.4:c.79894G>C
NM_133378.4:c.99385G>C
NM_133432.3:c.80269G>C
NM_133437.4:c.80470G>C
NP_001243779.1:p.Glu34056Gln
NP_001254479.2:p.Glu35697Gln
NP_003310.4:p.Glu26632Gln
NP_596869.4:p.Glu33129Gln
NP_597676.3:p.Glu26757Gln
NP_597681.4:p.Glu26824Gln
LRG_391:g.307141G>C
NC_000002.11:g.179393389C>G
NM_001267550.1:c.107089G>C
NM_003319.4:c.79894G>C

Protein change:

E26632Q

Links:

dbSNP: rs199531140

NCBI 1000 Genomes Browser:

rs199531140

Molecular consequence:

NM_001256850.1:c.102166G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.107089G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.79894G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.99385G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.80269G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.80470G>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
SCV000271129	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jul 9, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001880207	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Benign (Apr 23, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766515	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 22, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271129

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jul 9, 2015)

germline

clinical testing

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

SCV001880207

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics criteria)

Benign
(Apr 23, 2021)

unknown

clinical testing

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

SCV002766515

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 22, 2022)

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	not provided	1	1	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	unknown	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 Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271129.3

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

Description

p.Glu33129Gln in exon 309 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (42/15700) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs199531140).

#	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 Athena Diagnostics, SCV001880207.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766515.1

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

Description

Variant summary: TTN c.99385G>C (p.Glu33129Gln) results in a conservative amino acid change located in the M-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 247288 control chromosomes (gnomAD), predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.99385G>C in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, four as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

#	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 24, 2024

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