NM_001267550.2(TTN):c.31735A>C (p.Lys10579Gln) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 10, 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:: RCV000222100.6

Allele description [Variation Report for NM_001267550.2(TTN):c.31735A>C (p.Lys10579Gln)]

NM_001267550.2(TTN):c.31735A>C (p.Lys10579Gln)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.31735A>C (p.Lys10579Gln)

HGVS:

NC_000002.12:g.178692043T>G
NG_011618.3:g.143760A>C
NM_001256850.1:c.30784A>C
NM_001267550.2:c.31735A>CMANE SELECT
NM_003319.4:c.13282+46039A>C
NM_133378.4:c.28003A>C
NM_133432.3:c.13657+46039A>C
NM_133437.4:c.13858+46039A>C
NP_001243779.1:p.Lys10262Gln
NP_001254479.2:p.Lys10579Gln
NP_596869.4:p.Lys9335Gln
LRG_391:g.143760A>C
NC_000002.11:g.179556770T>G
NM_001267550.1:c.31735A>C

Protein change:

K10262Q

Links:

dbSNP: rs376287951

NCBI 1000 Genomes Browser:

rs376287951

Molecular consequence:

NM_003319.4:c.13282+46039A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_133432.3:c.13657+46039A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_133437.4:c.13858+46039A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001256850.1:c.30784A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.31735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.28003A>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
SCV000272622	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 25, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004223688	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 10, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272622

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jun 25, 2015)

germline

clinical testing

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

SCV004223688

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 10, 2023)

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	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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272622.3

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

Description

The p.Lys9335Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 7/8600 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s376287951). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Lys9335Gln variant is uncertain.

#	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, SCV004223688.1

#	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.28003A>C (p.Lys9335Gln) results in a conservative amino acid change located in the I-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 8e-05 in 248950 control chromosomes. To our knowledge, no occurrence of c.28003A>C in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J, or other TTN-related diseases and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; 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: Apr 13, 2025

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