VCV002108499.4 - ClinVar

NM_001267550.2(TTN):c.106783A>G (p.Lys35595Glu)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (1)

This classification is based on the single submission received

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001267550.2(TTN):c.106783A>G (p.Lys35595Glu)

Variation ID: 2108499 Accession: VCV002108499.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.2 2: 178528968 (GRCh38) [ NCBI UCSC ] 2: 179393695 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 23, 2026	Mar 17, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001267550.2:c.106783A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001254479.2:p.Lys35595Glu	missense
NM_001256850.1:c.101860A>G	NP_001243779.1:p.Lys33954Glu	missense
NM_003319.4:c.79588A>G	NP_003310.4:p.Lys26530Glu	missense
NM_133378.4:c.99079A>G	NP_596869.4:p.Lys33027Glu	missense
NM_133432.3:c.79963A>G	NP_597676.3:p.Lys26655Glu	missense
NM_133437.4:c.80164A>G	NP_597681.4:p.Lys26722Glu	missense
NC_000002.12:g.178528968T>C
NC_000002.11:g.179393695T>C
NG_011618.3:g.306835A>G
NG_051363.1:g.11142T>C
LRG_391:g.306835A>G
LRG_391t1:c.106783A>G	LRG_391p1:p.Lys35595Glu

... more HGVS ... less HGVS

Protein change

K33954E, K33027E, K26530E, K26655E, K26722E, K35595E

Other names

Canonical SPDI

NC_000002.12:178528967:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA349403106 dbSNP: rs2468306493 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TTN		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	15032	40093
TTN-AS1	-	-	-	GRCh38	-	23015

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive limb-girdle muscular dystrophy type 2J Dilated cardiomyopathy 1G	Uncertain significance (1)	criteria provided, single submitter	Mar 17, 2022	RCV003034210.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 17, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Dilated cardiomyopathy 1G Autosomal recessive limb-girdle muscular dystrophy type 2J Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003328690.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 23975875‚ 25589632 Comment: show This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 35595 of the TTN protein (p.Lys35595Glu). This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 35595 of the TTN protein (p.Lys35595Glu). This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.	Roberts AM	Science translational medicine	2015	PMID: 25589632
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy.	Ceyhan-Birsoy O	Neurology	2013	PMID: 23975875

Text-mined citations for rs2468306493 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026