NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys) AND Dyskeratosis congenita

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 12, 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:: RCV001054196.9

Allele description [Variation Report for NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)]

NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)

Gene:

TINF2:TERF1 interacting nuclear factor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q12

Genomic location:

Preferred name:

NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)

Other names:

p.Arg282Cys

HGVS:

NC_000014.9:g.24240636G>A
NG_016650.1:g.7039C>T
NG_054634.1:g.13220G>A
NM_001099274.3:c.844C>TMANE SELECT
NM_001363668.2:c.739C>T
NM_012461.3:c.844C>T
NP_001092744.1:p.Arg282Cys
NP_001350597.1:p.Arg247Cys
NP_036593.2:p.Arg282Cys
LRG_342t1:c.844C>T
LRG_342t2:c.844C>T
LRG_342:g.7039C>T
LRG_342p1:p.Arg282Cys
LRG_342p2:p.Arg282Cys
NC_000014.8:g.24709842G>A
NM_001099274.1:c.844C>T

Protein change:

R247C; ARG282CYS

Links:

OMIM: 604319.0004; dbSNP: rs121918545

NCBI 1000 Genomes Browser:

rs121918545

Molecular consequence:

NM_001099274.3:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363668.2:c.739C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012461.3:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dyskeratosis congenita
Identifiers:: MONDO: MONDO:0015780; MedGen: C0265965; OMIM: PS127550

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001218499	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002678402	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 30, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18669893, 19090550, 21477109, 29742735 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001218499

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 12, 2021)

germline

clinical testing

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

SCV002678402

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 30, 2018)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes.

Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I.

Blood. 2008 Nov 1;112(9):3594-600. doi: 10.1182/blood-2008-05-153445. Epub 2008 Jul 30.

PubMed [citation]

PMID:: 18669893
PMCID:: PMC2572788

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001218499.3

#	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 Ambry Genetics, SCV002678402.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.R282C pathogenic mutation (also known as c.844C>T), located in coding exon 6 of the TINF2 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in multiple individuals with a clinical diagnosis of dyskeratosis congenita; most cases were reportedly de novo (paternity not confirmed); however, some individuals inherited the mutation from an affected parent (Walne AJ et al. Blood, 2008 Nov;112:3594-600; Du H et al. Medicine (Baltimore), 2018 May;97:e0724). This mutation was also described in two unrelated children with severe aplastic anemia (Du HY et al. Pediatr Blood Cancer, 2009 May;52:687). In addition, the most common TINF2 mutation, p.R282H, occurs at the same codon (Sasa GS et al. Clin. Genet., 2012 May;81:470-8). Based on the supporting evidence, p.R282C is interpreted as a disease-causing mutation.

#	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: Nov 24, 2024

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