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NM_001267550.2(TTN):c.39212-9C>A AND not specified

Germline classification:
Benign/Likely benign (2 submissions)
Last evaluated:
Aug 23, 2021
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:
RCV000156462.6

Allele description [Variation Report for NM_001267550.2(TTN):c.39212-9C>A]

NM_001267550.2(TTN):c.39212-9C>A

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.39212-9C>A
HGVS:
  • NC_000002.12:g.178652188G>T
  • NG_011618.3:g.183615C>A
  • NM_001256850.1:c.34691-9C>A
  • NM_001267550.2:c.39212-9C>AMANE SELECT
  • NM_003319.4:c.13283-9871C>A
  • NM_133378.4:c.31910-9C>A
  • NM_133432.3:c.13658-9871C>A
  • NM_133437.4:c.13859-9871C>A
  • LRG_391:g.183615C>A
  • NC_000002.11:g.179516915G>T
Links:
dbSNP: rs373056460
NCBI 1000 Genomes Browser:
rs373056460
Molecular consequence:
  • NM_001256850.1:c.34691-9C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001267550.2:c.39212-9C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_003319.4:c.13283-9871C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133378.4:c.31910-9C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.13658-9871C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.13859-9871C>A - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000206181Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely benign
(Feb 13, 2019) 		germlineclinical testing

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

SCV001821376Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Benign
(Aug 23, 2021) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot providednot providedclinical 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, SCV000206181.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The c.31910-9C>A variant in TTN is classified as likely benign because it has been identified in 0.095% (33/34446) of Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org) and computational tools do not suggest an impact on splicing. ACMG/AMP Criteria applied: BS1, BP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821376.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: TTN c.31910-9C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 248766 control chromosomes, predominantly at a frequency of 0.00096 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.31910-9C>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1504C>T, p.Arg502Trp; Internal testing), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 11, 2025