rs398122965

Positions:

chr16-2496872-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_001199107.2(TBC1D24):c.724C>T(p.Arg242Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 3.90

Variant links:

Genes affected

TBC1D24 (HGNC:29203): (TBC1 domain family member 24) This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

TBC1D24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain Rab-GAP TBC (size 215) in uniprot entity TBC24_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_001199107.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2496873-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

PP5

Variant 16-2496872-C-T is Pathogenic according to our data. Variant chr16-2496872-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496872-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 linkuse as main transcript	c.724C>T	p.Arg242Cys	missense_variant	2/8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1 linkuse as main transcript	c.724C>T	p.Arg242Cys	missense_variant	2/8		NM_001199107.2	ENSP00000494678	A1	Q9ULP9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249378

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000882

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DOORS syndrome

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, no assertion criteria provided	literature only	Division of Medical Genetics; Sainte-Justine Hospital	Dec 22, 2014	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jan 01, 2014	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Developmental and epileptic encephalopathy, 16

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 10, 2021	ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM3 strong, PP3 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2018

The p.R242C pathogenic mutation (also known as c.724C>T), located in coding exon 1 of the TBC1D24 gene, results from a C to T substitution at nucleotide position 724. The arginine at codon 242 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was identified in the homozgous and compound heterozygous states in multiple individuals with DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome) (Campeau PM et al. Lancet Neurol, 2014 Jan;13:44-58). Two cell lines expressing this mutation demonstrated shorter neurite length compared to wild type (Balestrini S et al. Neurology, 2016 Jul;87:77-85; Finelli MJ et al. Hum. Mol. Genet., 2018 Oct; doi.org/10.1093/hmg/ddy370). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

TBC1D24-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

The TBC1D24 c.724C>T variant is predicted to result in the amino acid substitution p.Arg242Cys. This variant was reported in the compound heterozygous or homozygous state in multiple individuals with DOORS syndrome (Campeau et al. 2014. PubMed ID: 24291220; Balestrini et al. 2016. PubMed ID: 27281533; Fernández-Marmiesse et al. 2019. PubMed ID: 31780880). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2546873-C-T). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2024

Published functional studies involving neuronal outgrowth assays of mouse cortical cells demonstrate a reduction in neurite length compared to wild-type (PMID: 27281533); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25169651, 24291220, 27281533, 28428906, 30579089, 31780880, 36147510, 31440721, 30335140) -

Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the TBC1D24 protein (p.Arg242Cys). This variant is present in population databases (rs398122965, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive TBC1D24-related conditions (PMID: 24291220, 31780880). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBC1D24 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TBC1D24 function (PMID: 27281533). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;T;T;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

.;.;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.7

M;M;M;.;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.9

D;.;D;.;.;.;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;.;D;.;.;D;D

Polyphen

1.0

D;D;D;.;.;D;.

Vest4

0.99

MutPred

0.72

Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);Loss of MoRF binding (P = 0.0041);

MVP

0.81

MPC

1.3, 1.7

ClinPred

0.98

GERP RS

4.2

Varity_R

0.83

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over