rs104894519

Positions:

chr16-11553576-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001136472.2(LITAF):c.334G>A(p.Gly112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G112D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LITAF
NM_001136472.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 5.69

Variant links:

Genes affected

LITAF (HGNC:16841): (lipopolysaccharide induced TNF factor) Lipopolysaccharide is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor-alpha (TNF-alpha) and other inflammatory mediators. This gene encodes lipopolysaccharide-induced TNF-alpha factor, which is a DNA-binding protein and can mediate the TNF-alpha expression by direct binding to the promoter region of the TNF-alpha gene. The transcription of this gene is induced by tumor suppressor p53 and has been implicated in the p53-induced apoptotic pathway. Mutations in this gene cause Charcot-Marie-Tooth disease type 1C (CMT1C) and may be involved in the carcinogenesis of extramammary Paget's disease (EMPD). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2014]

LITAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001136472.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 16-11553576-C-T is Pathogenic according to our data. Variant chr16-11553576-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-11553576-C-T is described in Lovd as [Pathogenic]. Variant chr16-11553576-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2 linkuse as main transcript	c.334G>A	p.Gly112Ser	missense_variant	3/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5 linkuse as main transcript	c.334G>A	p.Gly112Ser	missense_variant	3/4	1	NM_001136472.2	P1	Q99732-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000855

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 1C

Pathogenic:6Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 112 of the LITAF protein (p.Gly112Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LITAF-related conditions (PMID: 12525712, 15122712, 15776429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6057). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LITAF function (PMID: 23576546, 25058650). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	The LITAF c.334G>A; p.Gly112Ser variant (rs104894519) is reported in the literature in several large families affected with Charcot-Marie-Tooth disease type 1C (Bennett 2004, Klein 2014, Latour 2006, Park 2022, Potulska-Chromik 2012, Saifi 2005, Street 2003). This variant is also reported in ClinVar (Variation ID: 6057), but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.820), and functional analyses of the variant protein show disrupted protein localization (Lacerda 2014, Zhu 2013). Based on available information, this variant is considered to be pathogenic. References: Bennett CL et al. SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve. Ann Neurol. 2004 May;55(5):713-20. PMID: 15122712. Klein CJ et al. Application of whole exome sequencing in undiagnosed inherited polyneuropathies. J Neurol Neurosurg Psychiatry. 2014 Nov;85(11):1265-72. PMID: 24604904. Lacerda AF et al. LITAF mutations associated with Charcot-Marie-Tooth disease 1C show mislocalization from the late endosome/lysosome to the mitochondria. PLoS One. 2014 Jul 24;9(7):e103454. PMID: 25058650. Latour P et al. SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations. J Peripher Nerv Syst. 2006 Jun;11(2):148-55. PMID: 16787513. Park J et al. Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation. Genes Genomics. 2022 Aug;44(8):1007-1016. PMID: 35608774. Potulska-Chromik A et al. Charcot-Marie-Tooth type 1C disease coexisting with progressive multiple sclerosis: a study of an overlapping syndrome. Folia Neuropathol. 2012;50(4):369-74. PMID: 23319192. Saifi GM et al. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat. 2005 Apr;25(4):372-83. PMID: 15776429. Street VA et al. Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology. 2003 Jan 14;60(1):22-6. PMID: 12525712. Zhu H et al. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol Biol Cell. 2013 Jun;24(11):1619-37, S1-3. PMID: 23576546. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2021	Published functional studies demonstrate that G112S alters the intracellular localization of LITAF protein as well as the production of exosomes (Zhu et al., 2013; Lacerda et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20301384, 15776429, 12525712, 27549087, 28981955, 15786462, 1407588, 2239969, 23319192, 23576546, 25058650, 15122712, 24604904, 32399692, 33359733, 30373780, 31211173, 31827005, 32665875, 28211240, 32376792) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 03, 2023	- -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2022

The c.334G>A (p.G112S) alteration is located in exon 3 (coding exon 2) of the LITAF gene. This alteration results from a G to A substitution at nucleotide position 334, causing the glycine (G) at amino acid position 112 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in numerous individuals or families with inherited peripheral neuropathy phenotypes, such as Charcot-Marie-Tooth disease (Street, 2003; Bennett, 2004; Saifi, 2005; Latour, 2006; Potulska-Chromik, 2012; Klein, 2014; Jerath, 2017; Khosa, 2020; Vogt, 2020; Volodarsky, 2021). Another alteration at the same codon, c.335G>C (p.G112A), has been detected in an individual with Charcot-Marie-Tooth 1C (Guimarães-Costa, 2017). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrated that the p.G112S alteration reduced secreted LITAF in exosomes (Zhu, 2013) and mislocalized from the late endosome/lysosome to the mitochondria (Lacerda, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

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

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

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

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.7

L;L;L;L;L;L;.;L;L;.;.;L;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.0

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

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

D;D;T;D;D;D;T;D;D;.;.;T;.;T

Polyphen

1.0

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

Vest4

0.92

MVP

1.0

MPC

0.65

ClinPred

1.0

GERP RS

5.4

Varity_R

0.85

gMVP

0.83

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