8-74360184-C-T

Variant names:

• chr8-74360184-C-T
• rs104894078
• NM_018972.4:c.358C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_018972.4(GDAP1):​c.358C>T​(p.Arg120Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,166 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. R120Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1 O:3
• Conservation: PhyloP100: 1.07
• Publications: 40 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_018972.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-74360185-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 662601.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 8-74360184-C-T is Pathogenic according to our data. Variant chr8-74360184-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4198.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	c.358C>T	p.Arg120Trp	missense_variant	Exon 3 of 6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.358C>T	p.Arg120Trp	missense_variant	Exon 3 of 6	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460014 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726482

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110314

Other (OTH) AF: 0.0000166 AC: 1 AN: 60318

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00000938 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Uncertain:1 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

May 02, 2024

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 (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21753178, 19782751) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GDAP1: PM1, PM2, PM5, PP1:Moderate, PS3:Moderate, PS4:Moderate, PP3 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GDAP1 c.358C>T; p.Arg120Trp variant (rs104894078), is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (CMT) disease and has been observed to cosegregate with autosomal dominant disease in several large kindreds (Claramunt 2005, Sivera 2010, Zimon 2011). This variant is found on a single chromosome in the Genome Aggregation Database (1/31398 alleles), indicating it is not a common polymorphism. The arginine at codon 120 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.879). Consistent with these predictions, functional assays demonstrate the variant protein fails to promote mitochondrial fusion like wildtype GDAP1 (Niemann 2009, Zimon 2011). Additionally, another amino acid substitution at the same codon (p.Arg120Gly) has been reported to segregate with autosomal dominant CMT in a large family and is considered disease-causing (Manganelli 2012), suggesting this codon is functionally important. Based on available information, the p.Arg120Trp variant is considered to be pathogenic. References: Claramunt R et al. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet. 2005 Apr;42(4):358-65. Manganelli F et al. A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family. J Peripher Nerv Syst. 2012 Sep;17(3):351-5. Niemann A et al. GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance. Neurobiol Dis. 2009 Dec;36(3):509-20. Sivera R et al. Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2010 Dec;15(4):334-44. Zimon M et al. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology. 2011 Aug 9;77(6):540-8. -

Sep 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional analysis showed that R120W impairs mitochondrial function (Zimon et al., 2011; Niemann et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15772096, 22546700, 23628762, 26525999, 20301641, 25168384, 28379183, 14561495, 28673555, 30373780, 33136338, 31589614, 29417091, 35153971, 31655048, 30669311, 35656516, 33187793, 19782751, 31827005, 32153140, 15805163, 21753178, 34323022, 33480199) -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2K Pathogenic:4 Uncertain:1 Other:1

Aug 09, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 05, 2016

Neurology Department, Peking University First Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 09, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GDAP1 c.358C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3) This variant is a single nucleotide change in exon 3/6 of the GDAP1 gene, which is predicted to change the amino acid arginine at position 120 in the protein to tryptophan. The variant has been reported multiple times in individuals with CMT disease and has been observed to segregate with autosomal dominant CMT disease in several families (PMID: 21753178, 15805163, 21199105). The variant is in dbSNP (rs104894078) but is rare in population databases (gnomAD 1/152152, 0 homozygote (PS4). Functional studies have shown that this variant impairs the mitochondrial fusion process and results in dysfunctional mitochondrial (PMID: 21753178, 19782751) (PS3). The variant has been reported in both ClinVar (Variation ID: 4198) and HGMD (Accession: CM032927) as pathogenic. Computational predictions support a deleterious effect on the gene or gene product (PP3). -

May 16, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease type 4A Pathogenic:3

Aug 10, 2023

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.358C>T (p.Arg120Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes. c.358C>T has been reported in the literature as segregating with a milder phenotype in multiple individuals affected with features of autosomal dominant Charcot-Marie Disease Type 4A (example, Claramunt_2005, Pezzini_2016). These data indicate that the variant is very likely to be associated with disease. Publications reporting an impact on protein function have been reported (example, Estela_2011). The following publications have been ascertained in the context of this evaluation (PMID: 33136338, 15805163, 21890626, 26525999). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 23, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM1,PM2,PP3. -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 120 of the GDAP1 protein (p.Arg120Trp). This variant is present in population databases (rs104894078, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 15805163, 21199105, 21753178). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 14561495); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 4198). 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 expected to disrupt GDAP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GDAP1 function (PMID: 18021315, 19782751, 21753178, 21890626). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 26, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R120W pathogenic mutation (also known as c.358C>T), located in coding exon 3 of the GDAP1 gene, results from a C to T substitution at nucleotide position 358. The arginine at codon 120 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R120W alteration has been reported to segregate with disease in multiple unrelated families with features of dominantly inherited Charcot-Marie-Tooth disease (CMT; Sivera R et al. J. Peripher. Nerv. Syst., 2010 Dec;15:334-44; Zimo M et al. Neurology, 2011 Aug;77:540-8; Vital A et al. Neuromuscul. Disord., 2012 Aug;22:735-41). Reported patients have a variable phenotype with mild-moderate axonal CMT with typical onset around adolescence, and incomplete penetrance has been reported (Sivera R et al. J. Peripher. Nerv. Syst., 2010 Dec;15:334-44; Vital A et al. Neuromuscul. Disord., 2012 Aug;22:735-41). The mechanism for disease of dominantly inherited forms of GDAP1-related CMT is an interference with mitochondrial fusion, and functional studies showed significant mitochondrial fragmentation and significantly impaired mitochondrial fusion in cells transfected with the p.R120W alteration compared to wildtype (Niemann A et al. Neurobiol. Dis., 2009 Dec;36:509-20; Zimo M et al. Neurology, 2011 Aug;77:540-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth disease recessive intermediate A;C1842983:Charcot-Marie-Tooth disease axonal type 2K;C1859198:Charcot-Marie-Tooth disease type 4A Pathogenic:1

Apr 20, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 3 of the GDAP1 gene that results in the amino acid substitution of Tryptophan for Arginine at codon 120 was detected. The observed variant c.358C>T(p.Arg120Trp) has previously been reported in heterozygous state in patients affected with Charcot-Marie-Tooth type 4A disease. Experimental studies have shown that this missense change impairs the mitochondrial fusion process and results in dysfunctional mitochondria (Pedrola et al. 2008). The variant has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be 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 Other:1

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 04-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;.
PhyloP100		1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.87		Loss of disorder (P = 0.0269);.;
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.47
gMVP		0.89
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894078; hg19: chr8-75272419; COSMIC: COSV99619748; COSMIC: COSV99619748;