8-74363051-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP2PP3PP5_Very_Strong

The NM_018972.4(GDAP1):c.692C>T(p.Pro231Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,312,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P231P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GDAP1
NM_018972.4 missense, splice_region

Scores

Splicing: ADA: 0.9956

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:2

Conservation

PhyloP100: 1.86

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2K
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Charcot-Marie-Tooth disease recessive intermediate A
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant Charcot-Marie-Tooth disease type 2K
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 4A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GDAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_018972.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0 (below the threshold of 3.09). Trascript score misZ: 1.1646 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease recessive intermediate A, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, autosomal dominant Charcot-Marie-Tooth disease type 2K.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 8-74363051-C-T is Pathogenic according to our data. Variant chr8-74363051-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4 link	c.692C>T	p.Pro231Leu	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000220822.12	NP_061845.2	Q8TB36-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12 link	c.692C>T	p.Pro231Leu	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_018972.4	ENSP00000220822.7		Q8TB36-1

Frequencies

GnomAD3 genomes

AF:

0.000165

AC:

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250094

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000138

AC:

AN:

1160338

Hom.:

Cov.:

AF XY:

0.00000507

AC XY:

AN XY:

592116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27752

American (AMR)

AF:

0.000203

AC:

AN:

44330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24270

East Asian (EAS)

AF:

0.00

AC:

AN:

38300

South Asian (SAS)

AF:

0.00

AC:

AN:

80160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5184

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836742

Other (OTH)

AF:

0.000119

AC:

AN:

50408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00164

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000760

Hom.:

Bravo

AF:

0.000280

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2K

Pathogenic:2Uncertain:1

Sep 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GDAP1 c.692C>T (p.Pro231Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 250094 control chromosomes (gnomAD). c.692C>T has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease and this variant co-segregated with the disease (Xin_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 18492089). ClinVar contains an entry for this variant (Variation ID: 4202). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Jan 09, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18492089, 21212451, 20849849, 34057104, 23628762, 20685671, 37966693, 39399040) -

Jul 19, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. 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

Pathogenic:1Uncertain:1

Inherited Neuropathy Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Aug 14, 2019

Genesis Genome Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Pathogenic:1

Jan 05, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.692C>T (p.P231L) alteration is located in exon 5 (coding exon 5) of the GDAP1 gene. This alteration results from a C to T substitution at nucleotide position 692, causing the proline (P) at amino acid position 231 to be replaced by a leucine (L)._x000D_ _x000D_ _x000D_ _x000D_ 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 0.002% (6/281404) total alleles studied. The highest observed frequency was 0.017% (6/35350) of Latino alleles. The p.P231L alteration was reported as homozygous in multiple individuals with clinical features consistent with GDAP1-related Charcot-Marie-Tooth disease (Xin, 2008; Ortiz-Santiago, 2021; Ambry internal data). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Charcot-Marie-Tooth disease type 4A

Pathogenic:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 231 of the GDAP1 protein (p.Pro231Leu). This variant is present in population databases (rs121908114, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 18492089; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4202). 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. -

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

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.35

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

L;.

PhyloP100

1.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.79

N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.039

D;D

Sift4G

Uncertain

0.044

D;T

Polyphen

0.95

P;.

Vest4

0.80

MutPred

0.79

Loss of loop (P = 0.0512);.;

MVP

1.0

MPC

1.3

ClinPred

0.65

GERP RS

4.8

Varity_R

0.24

gMVP

0.60

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over