rs104894079

Variant names:

• chr8-74360295-A-C
• rs104894079
• NM_018972.4:c.469A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_018972.4(GDAP1):​c.469A>C​(p.Thr157Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T157T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1 O:1
• Conservation: PhyloP100: 4.98
• Publications: 11 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_018972.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.939
• PP5: Variant 8-74360295-A-C is Pathogenic according to our data. Variant chr8-74360295-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4199.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.469A>C	p.Thr157Pro	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.469A>C	p.Thr157Pro	missense_variant	Exon 3 of 6	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4A Pathogenic:1 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

- -

Dec 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with proline at codon 157 of the GDAP1 protein (p.Thr157Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Charcot-Marie-Tooth disease (PMID: 15805163), which is consistent with an autosomal dominant pattern of inheritance. ClinVar contains an entry for this variant (Variation ID: 4199). This variant has been reported to affect GDAP1 protein function via a dominant-negative or gain-of-function mechanism (PMID: 19782751, 23628762, 21890626, 18021315, 28220846). For these reasons, this variant has been classified as Pathogenic. -

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

Apr 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;.
PhyloP100		5.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	1.6	N;N
REVEL	Pathogenic	0.77
Sift	Benign	0.23	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.92	P;.
Vest4		0.88
MutPred		0.84		Loss of helix (P = 0.0237);.;
MVP		0.99
MPC		0.86
ClinPred		0.76	D
GERP RS		5.5
Varity_R		0.29
gMVP		0.84
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894079; hg19: chr8-75272530;