NM_001199107.2(TBC1D24):c.724C>T (p.Arg242Cys) AND DOORS syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 1, 2014
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:: RCV000076913.20

Allele description [Variation Report for NM_001199107.2(TBC1D24):c.724C>T (p.Arg242Cys)]

NM_001199107.2(TBC1D24):c.724C>T (p.Arg242Cys)

Gene:

TBC1D24:TBC1 domain family member 24 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_001199107.2(TBC1D24):c.724C>T (p.Arg242Cys)

Other names:

p.R242C:CGC>TGC

HGVS:

NC_000016.10:g.2496872C>T
NG_028170.1:g.26727C>T
NM_001199107.1:c.[724C>T]
NM_001199107.2:c.724C>TMANE SELECT
NM_020705.3:c.724C>T
NP_001186036.1:p.Arg242Cys
NP_001186036.1:p.Arg242Cys
NP_065756.1:p.Arg242Cys
NC_000016.9:g.2546873C>T
NM_001199107.1:c.724C>T
NM_001199107.1:c.[724C>T]
NM_001199107.2:c.724C>T
NM_020705.2:c.724C>T
Q9ULP9:p.Arg242Cys

Protein change:

R242C; ARG242CYS

Links:

UniProtKB: Q9ULP9#VAR_070915; OMIM: 613577.0007; dbSNP: rs398122965

NCBI 1000 Genomes Browser:

rs398122965

Molecular consequence:

NM_001199107.2:c.724C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020705.3:c.724C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: DOORS syndrome (DOORS)
Synonyms:: Deafness onychodystrophy osteodystrophy and mental retardation syndrome; DRC SYNDROME; BRACHYDACTYLY DUE TO ABSENCE OF DISTAL PHALANGES; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009079; MedGen: C0795934; Orphanet: 3231; Orphanet: 79500; OMIM: 220500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000108710	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000211967	Division of Medical Genetics; Sainte-Justine Hospital	no assertion criteria provided	Pathogenic (Dec 22, 2014)	germline	literature only	Citation Link,
SCV000266460	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Campeau et al. (Lancet Neurol 2014))	Pathogenic (Jan 1, 2014)	germline	research	PubMed (5) [See all records that cite these PMIDs] 25169651, 25719194, 23806086, 24088043, 24291220
SCV002073120	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002106361	GeneReviews	no classification provided	not provided	germline	literature only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	9	not provided	not provided	not provided	not provided	research
not provided	germline	yes	7	5	not provided	not provided	yes	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome.

Campeau PM, Hennekam RC; DOORS syndrome collaborative group..

Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):327-32. doi: 10.1002/ajmg.c.31412. Epub 2014 Aug 28.

PubMed [citation]

PMID:: 25169651

TBC1D24-Related Disorders.

Balestrini S, Campeau PM, Mei D, Guerrini R, Sisodiya S.

2015 Feb 26 [updated 2024 Oct 24]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 25719194

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000108710.4

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

Description

In 4 affected individuals from 3 unrelated families with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500), Campeau et al. (2014) identified a homozygous c.724C-T transition in the TBC1D24 gene, resulting in an arg242-to-cys (R242C) substitution. The families were from the United States, India, and Brazil. Three affected individuals from 2 additional families were compound heterozygous for R242C and another mutation in the TBC1D24 gene: R40C (613577.0008) or Q20E (613577.0009). The mutations in the first families were found by whole-exome sequencing and confirmed by Sanger sequencing. All substitutions occurred at conserved residues and were not found in the Exome Variant Server database.

#	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		not provided	not provided	not provided	not provided

From Division of Medical Genetics; Sainte-Justine Hospital, SCV000211967.1

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

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

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000266460.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	yes	research	PubMed (5)
2	not provided	9	not provided	not provided	research	PubMed (5)

Description

We identified 26 families with DOORS syndrome; each patient had at least 3 of the 5 well-described features of DOORS syndrome, which include deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. A combination of whole-exome sequencing and Sanger sequencing identified homozygous or compound heterozygous pathogenic variants in TBC1D24 in 11 individuals from 9 families.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		7	not provided	5	not provided
2	germline	no	not provided	not provided	not provided		9	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV002073120.1

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

Description

The missense variant p.R242C in TBC1D24 (NM_001199107.2) has been reported previously in affected individuals with DOORS syndrome (Campeau PM et al). Functional studies reveal a damaging effect (Balestrini S et al). The variant has been submitted to ClinVar as Pathogenic. The p.R242C variant is observed in 1/15,478 (0.0065%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R242C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 242 of TBC1D24 is conserved in all mammalian species. The nucleotide c.724 in TBC1D24 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

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

From GeneReviews, SCV002106361.2

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

#	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 10, 2024

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