NM_001267550.2(TTN):c.81899G>A (p.Arg27300His) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Apr 9, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV000040674.16

Allele description [Variation Report for NM_001267550.2(TTN):c.81899G>A (p.Arg27300His)]

NM_001267550.2(TTN):c.81899G>A (p.Arg27300His)

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.81899G>A (p.Arg27300His)

Other names:

p.R25659H:CGT>CAT

HGVS:

NC_000002.12:g.178564233C>T
NG_011618.3:g.271570G>A
NG_051363.1:g.46407C>T
NM_001256850.1:c.76976G>A
NM_001267550.2:c.81899G>AMANE SELECT
NM_003319.4:c.54704G>A
NM_133378.4:c.74195G>A
NM_133432.3:c.55079G>A
NM_133437.4:c.55280G>A
NP_001243779.1:p.Arg25659His
NP_001254479.2:p.Arg27300His
NP_003310.4:p.Arg18235His
NP_596869.4:p.Arg24732His
NP_597676.3:p.Arg18360His
NP_597681.4:p.Arg18427His
LRG_391:g.271570G>A
NC_000002.11:g.179428960C>T
NM_001267550.1:c.81899G>A
Q8WZ42:p.Arg25659His
c.74195G>A

Protein change:

R18235H

Links:

UniProtKB: Q8WZ42#VAR_040264; dbSNP: rs55850344

NCBI 1000 Genomes Browser:

rs55850344

Molecular consequence:

NM_001256850.1:c.76976G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.81899G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.54704G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.74195G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.55079G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.55280G>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
SCV000064365	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Mar 6, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001879709	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Likely benign (Jan 11, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28771489, 28166282, 26467025
SCV002766501	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26516846, 28255936 Citation Link,
SCV006066802	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 9, 2025)	germline	clinical testing	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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	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
not provided	germline	unknown	not provided	not provided	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

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.

Mademont-Soler I, Mates J, Yotti R, Espinosa MA, Pérez-Serra A, Fernandez-Avila AI, Coll M, Méndez I, Iglesias A, Del Olmo B, Riuró H, Cuenca S, Allegue C, Campuzano O, Picó F, Ferrer-Costa C, Álvarez P, Castillo S, Garcia-Pavia P, Gonzalez-Lopez E, Padron-Barthe L, Díaz de Bustamante A, et al.

PLoS One. 2017;12(8):e0181465. doi: 10.1371/journal.pone.0181465.

PubMed [citation]

PMID:: 28771489
PMCID:: PMC5542623

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064365.6

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

Description

Arg24732His in exon 275 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals (guinea pig, hedgehog, elephant, rock hyrax, and platypus) have a histidine (His) at this position, despite high nearby amino acid conserv ation. In addition, computational analyses (biochemical properties, AlignGVGD, a nd PolyPhen2) do not suggest a high likelihood of impact to the protein. This va riant has been identified in 5/8226 European American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs55850344).

#	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 Athena Diagnostics, SCV001879709.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766501.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: TTN c.74195G>A (p.Arg24732His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 247888 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00037 vs 0.00063), allowing no conclusion about variant significance. c.74195G>A has been reported in the literature in individuals who suffered a sudden unexplained cardiac death (e.g. Campuzano_2015, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 28255936). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. 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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV006066802.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 25, 2025

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