rs104894080

Positions:

chr8-74364005-C-T

Variant summary

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

The NM_018972.4(GDAP1):c.715C>T(p.Leu239Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,613,944 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 (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

GDAP1
NM_018972.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:3O:1

Conservation

PhyloP100: 3.69

Variant links:

Genes affected

GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

GDAP1 links:

GDAP1 (HGNC:):

GDAP1 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 GST C-terminal (size 156) in uniprot entity GDAP1_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_018972.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 8-74364005-C-T is Pathogenic according to our data. Variant chr8-74364005-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-74364005-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP1	NM_018972.4 linkuse as main transcript	c.715C>T	p.Leu239Phe	missense_variant	6/6	ENST00000220822.12	NP_061845.2	Q8TB36-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12 linkuse as main transcript	c.715C>T	p.Leu239Phe	missense_variant	6/6	1	NM_018972.4	ENSP00000220822.7		Q8TB36-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251444

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727200

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:

0.0000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000996

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4A

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was detected in homozygous state. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 239 of the GDAP1 protein (p.Leu239Phe). This variant is present in population databases (rs104894080, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 14561495, 17433678, 18504680, 18991200, 19500985, 20232219, 25231362). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 20232219). ClinVar contains an entry for this variant (Variation ID: 4200). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	Published functional studies demonstrate that the variant results in protein mislocalization (Rzepnikowska et al., (2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18991200, 14561495, 17433678, 18504680, 20232219, 19500985, 17039978, 27549087, 29372391, 29858556, 32183277, 33477664, 31589614, 20685671, 20849849, 23628762, 32376792) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GDAP1: PM3:Very Strong, PP1:Strong, PM1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with autosomal recessive Charcot-Marie-Tooth disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

Charcot-Marie-Tooth disease axonal type 2K

Pathogenic:1Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Oct 03, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Mar 01, 2022	- -

Charcot-Marie-Tooth disease recessive intermediate A

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -

Charcot-Marie-Tooth disease

Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Sensory neuropathy;C0152025:Polyneuropathy;C0241005:Elevated circulating creatine kinase concentration;C1263857:Peripheral axonal neuropathy;C1314665:Elevated circulating alkaline phosphatase concentration

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 02, 2015

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.715C>T (p.L239F) alteration is located in exon 6 (coding exon 6) of the GDAP1 gene. This alteration results from a C to T substitution at nucleotide position 715, causing the leucine (L) at amino acid position 239 to be replaced by a phenylalanine (F). Based on the available evidence, the GDAP1 c.715C>T (p.L239F) alteration is classified as pathogenic for autosomal recessive GDAP1-related Charcot-Marie-Tooth disease; however, it is unlikely to be causative of autosomal dominant GDAP1-related Charcot-Marie-Tooth disease, type 2. Based on data from gnomAD, the T allele has an overall frequency of 0.004% (10/282836) total alleles studied. The highest observed frequency was 0.008% (10/129150) of European (non-Finnish) alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in GDAP1 in multiple individuals with autosomal recessive GDAP1-related Charcot-Marie-Tooth disease (Kabziska, 2010; Barankova, 2007; Moroni, 2009; Rougeot, 2008; Auer-Grumbach, 2008; Kabziska, 2014). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest this variant disrupts mitochondrial and golgi function in yeast and human cells; however, the physiological relevance of these findings is unclear (Rzepnikowska, 2020; Binida, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

GDAP1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 20, 2018

The GDAP1 c.715C>T (p.Leu239Phe) missense variant has been reported in at least six studies and is found in a total of 21 probands with autosomal recessive Charcot-Marie-Tooth disease (CMT), including five in a homozygous state, 15 in a compound heterozygous state, and one in a heterozygous state without a second variant identified (Ammar et al. 2003, Kabzinska et al. 2003, Barankova et al. 2007, Auer-Grumbach et al. 2008, Moroni et al. 2009, Kabzinska et al. 2010). Ammar et al. (2003) identified the c.715C>T (p.Leu239Phe) variant in a compound heterozygous state with a frameshift variant in two siblings with CMT. Their unaffected mother carried the p.Leu239Phe variant and their unaffected father carried the frameshift variant. The p.Leu239Phe variant was absent from 158 controls and is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. Haplotype analysis suggests that the p.Leu239Phe variant is likely a founder mutation in the central and eastern European population (Kabzinska et al. 2010). Based on the collective evidence, the p.Leu239Phe variant classified as pathogenic for GDAP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Charcot-Marie-Tooth disease recessive intermediate A;C1842983:Charcot-Marie-Tooth disease axonal type 2K;C1843183:Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive;C1859198:Charcot-Marie-Tooth disease type 4A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.92

MVP

0.97

MPC

1.4

ClinPred

0.89

GERP RS

5.0

Varity_R

0.92

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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