NM_001267550.2(TTN):c.107889del (p.Lys35963fs) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Nov 22, 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:: RCV000184369.17

Allele description [Variation Report for NM_001267550.2(TTN):c.107889del (p.Lys35963fs)]

NM_001267550.2(TTN):c.107889del (p.Lys35963fs)

Genes:

TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.107889del (p.Lys35963fs)

HGVS:

NC_000002.12:g.178527101del
NG_011618.3:g.308704del
NG_051363.1:g.9275del
NM_001256850.1:c.102966del
NM_001267550.2:c.107889delMANE SELECT
NM_003319.4:c.80694del
NM_133378.4:c.100185del
NM_133432.3:c.81069del
NM_133437.4:c.81270del
NP_001243779.1:p.Lys34322fs
NP_001254479.2:p.Lys35963fs
NP_003310.4:p.Lys26898fs
NP_596869.4:p.Lys33395fs
NP_597676.3:p.Lys27023fs
NP_597681.4:p.Lys27090fs
LRG_391t1:c.107889del
LRG_391:g.308704del
NC_000002.11:g.179391826del
NC_000002.11:g.179391828del
NM_001256850.1:c.102966delA
NM_001267550.1:c.107889del
NM_001267550.2:c.107889delAMANE SELECT
NM_003319.4:c.80694delA
NM_133378.4:c.100185del
NM_133378.4:c.100185delA
p.K34322NfsX9
p.Lys35963AsnfsTer9

Nucleotide change:

AJ277892.2:g.293378delA

Protein change:

K26898fs

Links:

dbSNP: rs281864930

NCBI 1000 Genomes Browser:

rs281864930

Molecular consequence:

NM_001256850.1:c.102966del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.107889del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.80694del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.100185del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.81069del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.81270del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000229485	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Aug 14, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18948003, 23975875, 24395473 N:\Bioinformatics\EmBase\data\INPUT\TTN interpretation.docx, Citation Link,
SCV000236994	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 22, 2021)	germline	clinical testing	Citation Link,
SCV001474957	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Mar 13, 2020)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18948003, 23975875, 24395473, 25037085, 26627873, 23446887, 26467025
SCV002022474	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002501556	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 20, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 18948003, 26516846, 31589614, 23975875, 26627873, 32403337, 32778822, 32039858, 32528171, 30238059, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	7	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

Atypical phenotypes in titinopathies explained by second titin mutations.

Evilä A, Vihola A, Sarparanta J, Raheem O, Palmio J, Sandell S, Eymard B, Illa I, Rojas-Garcia R, Hankiewicz K, Negrão L, Löppönen T, Nokelainen P, Kärppä M, Penttilä S, Screen M, Suominen T, Richard I, Hackman P, Udd B.

Ann Neurol. 2014 Feb;75(2):230-40. doi: 10.1002/ana.24102. Epub 2014 Feb 24.

PubMed [citation]

PMID:: 24395473

Congenital myopathies and muscular dystrophies.

Gilbreath HR, Castro D, Iannaccone ST.

Neurol Clin. 2014 Aug;32(3):689-703, viii. doi: 10.1016/j.ncl.2014.04.006. Review.

PubMed [citation]

PMID:: 25037085

See all PubMed Citations (15)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000229485.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (3)

#	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		7	not provided	not provided	not provided

From GeneDx, SCV000236994.14

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

Description

Reported as g.293378delA in the heterozygous state in individuals from two Spanish families with tibial muscular dystrophy (TMD) (Hackman et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation as the last 29 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 20301498, 23975875, 18948003, 26627873, 26516846, 27854229, 24395473, 30238059, 31589614, 32528171, 32403337, 32039858)

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

From Athena Diagnostics, SCV001474957.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

#	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 Revvity Omics, Revvity, SCV002022474.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002501556.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

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

Last Updated: Oct 20, 2024

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