NM_001267550.2(TTN):c.104399del (p.Arg34800fs) AND TTN-related myopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 2, 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:: RCV003225939.3

Allele description [Variation Report for NM_001267550.2(TTN):c.104399del (p.Arg34800fs)]

NM_001267550.2(TTN):c.104399del (p.Arg34800fs)

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.104399del (p.Arg34800fs)

Other names:

NM_001267550.2(TTN):c.104399del; p.Arg34800fs

HGVS:

NC_000002.12:g.178532216del
NG_011618.3:g.303587del
NG_051363.1:g.14390del
NM_001256850.1:c.99476del
NM_001267550.2:c.104399delMANE SELECT
NM_003319.4:c.77204del
NM_133378.4:c.96695del
NM_133432.3:c.77579del
NM_133437.4:c.77780del
NP_001243779.1:p.Arg33159fs
NP_001254479.2:p.Arg34800fs
NP_003310.4:p.Arg25735fs
NP_596869.4:p.Arg32232fs
NP_597676.3:p.Arg25860fs
NP_597681.4:p.Arg25927fs
LRG_391:g.303587del
NC_000002.11:g.179396943del
NC_000002.12:g.178532216delC
NM_001256850.1:c.99476delG
NM_001267550.2:c.104399del
NM_003319.4:c.77204delG

Protein change:

R25735fs

Links:

dbSNP: rs747662439

NCBI 1000 Genomes Browser:

rs747662439

Molecular consequence:

NM_001256850.1:c.99476del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.104399del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.77204del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.96695del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.77579del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.77780del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003922159	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 2, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003922159

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 2, 2023)

germline

curation

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

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	curation

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, SCV003922159.1

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

Description

The heterozygous p.Arg34800LysfsTer10 variant in TTN was identified by our study in two siblings with limb girdle muscular dystrophy. Familial exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 1678017). The p.Arg34800LysfsTer10 variant in TTN has not been previously reported in individuals with autosomal recessive limb girdle muscular dystrophy 10 but has been identified in 0.004% (1/24756) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs747662439). 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: 288119) and has conflicting interpretations of pathogenicity. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 34800 and leads to a premature termination codon 10 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 limb girdle muscular dystrophy 10. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive limb girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).

#	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: Sep 29, 2024

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