rs104894079

Positions:

• chr8-74360295-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The ENST00000220822.12(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 ENST00000220822.12 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1 O:1
• Conservation: PhyloP100: 4.98

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000220822.12
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 4199.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-74360295-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.469A>C	p.Thr157Pro	missense_variant	3/6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.469A>C	p.Thr157Pro	missense_variant	3/6	1	NM_018972.4	ENSP00000220822	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2018	For these reasons, this variant has been classified as Pathogenic. 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). 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 is not present in population databases (ExAC no frequency). 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. -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Charcot-Marie-Tooth disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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;.
MutationTaster	Benign	1.0	A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894079; hg19: chr8-75272530;