8-74360173-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_018972.4(GDAP1):​c.347T>G​(p.Met116Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,594 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. M116T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GDAP1
NM_018972.4 missense

Scores

4
4
11

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:2O:2

Conservation

PhyloP100: 3.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-74360173-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.86
PP5
Variant 8-74360173-T-G is Pathogenic according to our data. Variant chr8-74360173-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-74360173-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GDAP1NM_018972.4 linkc.347T>G p.Met116Arg missense_variant Exon 3 of 6 ENST00000220822.12 NP_061845.2 Q8TB36-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GDAP1ENST00000220822.12 linkc.347T>G p.Met116Arg missense_variant Exon 3 of 6 1 NM_018972.4 ENSP00000220822.7 Q8TB36-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152226
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251466
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135906
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461368
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727046
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000384
Hom.:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:2Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Dec 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 29, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 38428336, 16607474, 32376792, 28837237, 25429913, 38374194, 36790232, 15377708, 20685671, 20849849, 23628762, 21965300) -

Charcot-Marie-Tooth disease type 4A Pathogenic:1Other:1
Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 116 of the GDAP1 protein (p.Met116Arg). This variant is present in population databases (rs281865060, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 15377708, 25429913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38411). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GDAP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect GDAP1 function (PMID: 21965300). For these reasons, this variant has been classified as Pathogenic. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Charcot-Marie-Tooth disease Uncertain:1Other:1
-
Inherited Neuropathy Consortium
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Peripheral neuropathy Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Jan 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2K Uncertain:1
Jan 06, 2016
Inherited Neuropathy Consortium Ii, University Of Miami
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.40
CADD
Benign
21
DANN
Benign
0.93
DEOGEN2
Benign
0.076
T;.
Eigen
Benign
-0.17
Eigen_PC
Benign
0.067
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.81
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
0.20
N;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
0.43
N;N
REVEL
Uncertain
0.56
Sift
Benign
0.52
T;T
Sift4G
Benign
0.10
T;T
Polyphen
0.0010
B;.
Vest4
0.85
MutPred
0.80
Gain of loop (P = 0.0097);.;
MVP
0.95
MPC
0.66
ClinPred
0.55
D
GERP RS
5.5
Varity_R
0.62
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs281865060; hg19: chr8-75272408; API