rs375431837

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_018972.4(GDAP1):c.845G>A(p.Arg282His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,056 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. R282C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GDAP1
NM_018972.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 9.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 11) in uniprot entity GDAP1_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_018972.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-74364134-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

PP5

Variant 8-74364135-G-A is Pathogenic according to our data. Variant chr8-74364135-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 574996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-74364135-G-A is described in Lovd as [Pathogenic]. Variant chr8-74364135-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-74364135-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	6/6	ENST00000220822.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDAP1	ENST00000220822.12 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	6/6	1	NM_018972.4	P3	Q8TB36-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251486

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000295

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the GDAP1 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in the compound heterozygous state in multiple individuals with autosomal recessive GDAP1-related Charcot-Marie-Tooth disease (Abe A et al. J Hum Genet, 2011 May;56:364-8; Lin KP et al. PLoS One, 2011 Dec;6:e29393; Wu R et al. Front Neurosci, 2021 Jul;15:705277; Yoshimura A et al. Clin Genet, 2017 Sep;92:274-280). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive spectrum of Charcot-Marie-Tooth diseases when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant axonal Charcot-Marie-Tooth disease, type 2K is unclear. -

Charcot-Marie-Tooth disease type 4A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in GDAP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12499475, 14561495, 18812441). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 574996). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 21326314, 22206013, 28495047). This variant is present in population databases (rs375431837, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the GDAP1 protein (p.Arg282His). -

GDAP1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The GDAP1 c.845G>A variant is predicted to result in the amino acid substitution p.Arg282His. This variant has been reported in individuals with autosomal recessive Charcot-Marie-Tooth disease (see for example, Abe et al. 2011. PubMed ID: 21326314; Lin et al. 2011. PubMed ID: 22206013; Fu et al. 2017. PubMed ID: 28495047; Wu et al. 2021. PubMed ID: 34366782). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. An alternative nucleotide change affecting the same amino acid (c.844C>T, p.Arg282Cys) has also been reported as causative for autosomal recessive Charcot-Marie-Tooth disease (Nelis et al. 2002. PubMed ID: 12499475; Sevilla et al. 2008. PubMed ID: 18812441; Correia and Santos. 2022. PubMed ID: 35316520). In summary, the c.845G>A (p.Arg282His) variant is interpreted as pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.80

D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.92

Sift

Benign

0.058

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.99

MPC

1.4

ClinPred

0.94

GERP RS

5.0

Varity_R

0.44

gMVP

0.89

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