NM_001267550.2(TTN):c.63578G>A (p.Arg21193His) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 24, 2025
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:: RCV000155828.5

Allele description [Variation Report for NM_001267550.2(TTN):c.63578G>A (p.Arg21193His)]

NM_001267550.2(TTN):c.63578G>A (p.Arg21193His)

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.63578G>A (p.Arg21193His)

HGVS:

NC_000002.12:g.178587731C>T
NG_011618.3:g.248072G>A
NG_051363.1:g.69905C>T
NM_001256850.1:c.58655G>A
NM_001267550.2:c.63578G>AMANE SELECT
NM_003319.4:c.36383G>A
NM_133378.4:c.55874G>A
NM_133432.3:c.36758G>A
NM_133437.4:c.36959G>A
NP_001243779.1:p.Arg19552His
NP_001254479.2:p.Arg21193His
NP_003310.4:p.Arg12128His
NP_596869.4:p.Arg18625His
NP_597676.3:p.Arg12253His
NP_597681.4:p.Arg12320His
LRG_391:g.248072G>A
NC_000002.11:g.179452458C>T
NM_001267550.1:c.63578G>A
NM_003319.4:c.36383G>A

Protein change:

R12128H

Links:

dbSNP: rs372267046

NCBI 1000 Genomes Browser:

rs372267046

Molecular consequence:

NM_001256850.1:c.58655G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.63578G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.36383G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.55874G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.36758G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.36959G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000205539	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 9, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005885341	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 24, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000205539

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 9, 2014)

germline

clinical testing

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

SCV005885341

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 24, 2025)

germline

clinical testing

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

Citation Link

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	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical 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

Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs.

Al-Shafai KN, Al-Hashemi M, Manickam C, Musa R, Selvaraj S, Syed N, Vempalli F, Ali M, Yacoub M, Estivill X.

Mol Genet Genomic Med. 2021 Jul;9(7):e1709. doi: 10.1002/mgg3.1709. Epub 2021 Jun 17.

PubMed [citation]

PMID:: 34137518
PMCID:: PMC8372065

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000205539.5

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

Description

The Arg18625His variant in TTN has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/8254 European American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Arg18625His variant.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005885341.1

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

Description

Variant summary: TTN c.55874G>A (p.Arg18625His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 247430 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8.5e-05 vs 0.00039), allowing no conclusion about variant significance. c.55874G>A has been reported in the literature as a VUS in a setting of multigene panel testing in at least one individual affected with Hypertrophic Cardiomyopathy. This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34137518). ClinVar contains an entry for this variant (Variation ID: 179044). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Mar 22, 2025

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