rs397515442

Positions:

• chr8-74360194-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_018972.4(GDAP1):​c.368A>G​(p.His123Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,398 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:2 O:1
• Conservation: PhyloP100: 8.89

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a helix (size 11) in uniprot entity GDAP1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_018972.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• PP5: Variant 8-74360194-A-G is Pathogenic according to our data. Variant chr8-74360194-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-74360194-A-G is described in Lovd as [Pathogenic]. Variant chr8-74360194-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.368A>G	p.His123Arg	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.368A>G	p.His123Arg	missense_variant	3/6	1	NM_018972.4	ENSP00000220822	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461398 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 09, 2011	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2016	The H123R pathogenic variant in the GDAP1 gene has been reported previously in multiple unrelatedfamilies with autosomal dominant Charcot-Marie-Tooth (CMT) disease (Zimon et al., 2011; Auranenet al., 2013; Pezzini et al., 2016) . The H123R variant has been determined to be a founder mutationin the Finnish population and accounts for up to 14% of Finnish individuals with a clinical diagnosis ofCMT2 (Auranen et al., 2013). The H123R variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This conservative amino acidsubstitution occurs at a position that is conserved in mammals and in silico analysis is inconsistent inits predictions as to whether or not the variant is damaging to the protein structure/function. Missensevariants in nearby residues (R120G, R120W, R120Q, Q122K, D129H) have been reported in theHuman Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting thefunctional importance of this region of the protein. We interpret H123R as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 25, 2014	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 123 of the GDAP1 protein (p.His123Arg). This missense change has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease and is associated with reduced penetrance (PMID: 21753178, 23456260, 23963299, 26525999). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Finnish ancestry (PMID: 21753178, 23456260, 23963299, 26525999). ClinVar contains an entry for this variant (Variation ID: 50558). 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. Experimental studies have shown that this missense change affects GDAP1 function (PMID: 28220846). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.81
Sift	Benign	0.083	T;T
Sift4G	Benign	0.080	T;T
Polyphen		0.80	P;.
Vest4		0.93
MutPred		0.54		Gain of methylation at H123 (P = 0.0345);.;
MVP		1.0
MPC		1.4
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.28
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515442; hg19: chr8-75272429;