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NM_001267550.2(TTN):c.38661_38665del (p.Lys12887fs) AND TTN-related myopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 1, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003225935.3

Allele description [Variation Report for NM_001267550.2(TTN):c.38661_38665del (p.Lys12887fs)]

NM_001267550.2(TTN):c.38661_38665del (p.Lys12887fs)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.38661_38665del (p.Lys12887fs)
Other names:
NM_001267550.2(TTN):c.38661_38665del; p.Lys12887fs
HGVS:
  • NC_000002.12:g.178653470TTTCT[1]
  • NG_011618.3:g.182325GAAAA[1]
  • NM_001256850.1:c.34523-932_34523-928del
  • NM_001267550.1:c.38661_38665del
  • NM_001267550.2:c.38661_38665delMANE SELECT
  • NM_003319.4:c.13283-11156_13283-11152del
  • NM_133378.4:c.31742-932_31742-928del
  • NM_133432.3:c.13658-11156_13658-11152del
  • NM_133437.4:c.13859-11156_13859-11152del
  • NP_001254479.2:p.Lys12887fs
  • LRG_391t1:c.38661_38665del
  • LRG_391:g.182325GAAAA[1]
  • NC_000002.11:g.179518197TTTCT[1]
  • NM_001267550.2:c.38661_38665del
  • NM_001267550.2:c.38661_38665delGAAAAMANE SELECT
Protein change:
K12887fs
Links:
dbSNP: rs1553775212
NCBI 1000 Genomes Browser:
rs1553775212
Molecular consequence:
  • NM_001267550.2:c.38661_38665del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001256850.1:c.34523-932_34523-928del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_003319.4:c.13283-11156_13283-11152del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133378.4:c.31742-932_31742-928del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.13658-11156_13658-11152del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.13859-11156_13859-11152del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
TTN-related myopathy
Identifiers:
MONDO: MONDO:0100175; MedGen: CN294812

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003922097Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(May 1, 2023) 		germlinecuration

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003922097.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The heterozygous p.Lys12887AsnfsTer6 variant in TTN was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 1027852), in two siblings with congenital myopathy. Familial exome analysis showed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 1027852). The p.Lys12887AsnfsTer6 variant in TTN has been previously reported in one individual with autosomal recessive titin-associated myopathy (PMID: 28040389), but has been identified in 0.0008% (2/264690) of chromosomes in TopMed. Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 226126) and has been classified as likely pathogenic by NeuroMeGen,Hospital Clinico Santiago de Compostela. The one affected individual previously reported was homozygous for the variant (PMID: 28040389), which increases the likelihood that the p.Lys12887AsnfsTer6 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 12887 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive titin-associated myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive titin-associated myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting (Richards 2015).

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

Last Updated: Apr 20, 2025