NM_018972.4:c.358C>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:19 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	NM_018972.4	MANE Select	c.358C>T	p.Arg120Trp	missense	Exon 3 of 6	NP_061845.2	Q8TB36-1
	GDAP1	NM_001040875.4		c.154C>T	p.Arg52Trp	missense	Exon 3 of 6	NP_001035808.1	Q8TB36-2
	GDAP1	NM_001362931.2		c.358C>T	p.Arg120Trp	missense	Exon 3 of 6	NP_001349860.1	A0A6Q8PH97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.358C>T	p.Arg120Trp	missense	Exon 3 of 6	ENSP00000220822.7	Q8TB36-1
	GDAP1	ENST00000434412.3	TSL:1	c.226C>T	p.Arg76Trp	missense	Exon 4 of 7	ENSP00000417006.3	A0A7I2RYU0
	GDAP1	ENST00000675463.1		c.358C>T	p.Arg120Trp	missense	Exon 3 of 7	ENSP00000502327.1	A0A6Q8PGS2

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
5	1	-	Charcot-Marie-Tooth disease axonal type 2K (7)
3	-	-	Charcot-Marie-Tooth disease type 4A (3)
1	-	-	Charcot-Marie-Tooth disease (2)
1	-	-	Charcot-Marie-Tooth disease recessive intermediate A;C1842983:Charcot-Marie-Tooth disease axonal type 2K;C1859198:Charcot-Marie-Tooth disease type 4A (1)
1	-	-	Inborn genetic diseases (1)
-	-	-	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 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	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;