rs556827873

Variant names:

• chr8-74363012-A-C
• NM_018972.4:c.653A>C

Your query was ambiguous. Multiple possible variants found:

• chr8-74363012-A-C
• chr8-74363012-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_018972.4(GDAP1):​c.653A>C​(p.Gln218Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,180 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q218E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain GST C-terminal (size 156) in uniprot entity GDAP1_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_018972.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-74363011-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.653A>C	p.Gln218Pro	missense_variant	Exon 5 of 6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.653A>C	p.Gln218Pro	missense_variant	Exon 5 of 6	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428180 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 712908

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace glutamine with proline at codon 218 of the GDAP1 protein (p.(Gln218Pro)). The glutamine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the C-terminal glutathione S-transferase domain. There is a moderate physicochemical difference between glutamine and proline. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). A different pathogenic missense variant at this position with a smaller physicochemical difference (p.Gln218Asp) has been shown to cause autosomal dominant Charcot-Marie-Tooth disease (PMID: 18231710, 26525999, 33477664). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM5, PM2_Supporting, PP3. -

not provided Uncertain:1

Aug 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20685671, 20849849, 23628762, 18231710, 26525999, 33477664) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.65		Loss of helix (P = 0.0104);.;
MVP		0.99
MPC		1.4
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-75275247;