rs1060500978

Positions:

• chr8-74364072-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018972.4(GDAP1):​c.786del​(p.Phe263LeufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDAP1 NM_018972.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:3
• Conservation: PhyloP100: 0.607

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-74364072-TG-T is Pathogenic according to our data. Variant chr8-74364072-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-74364072-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4	c.786del	p.Phe263LeufsTer22	frameshift_variant	6/6	ENST00000220822.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDAP1	ENST00000220822.12	c.786del	p.Phe263LeufsTer22	frameshift_variant	6/6	1	NM_018972.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4A Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 21, 2021	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CMT Laboratory, Bogazici University	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 02, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GDAP1 protein in which other variant(s) (p.Arg341Glnfs*12) have been determined to be pathogenic (PMID: 25614874). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 406136). This premature translational stop signal has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 12499475). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe263Leufs*22) in the GDAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the GDAP1 protein. -

Charcot-Marie-Tooth disease recessive intermediate A Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous p.Phe263LeufsTer22 variant in GDAP1 was identified by our study in one individual with peripheral neuropathy. The p.Phe263LeufsTer22 variant in GDAP1 has been previously reported in 9 unrelated individuals with Charcot-Marie-Tooth disease type 4A (PMID: 34476298, PMID: 30373780, PMID: 34169998, PMID: 12499475, ClinVar SCV002059082.1) and segregated with disease in 9 affected relatives from four families (PMID: 12499475, PMID: 34476298). These 9 previously reported unrelated individuals were homozygotes, which increases the likelihood that the p.Phe263LeufsTer22 variant in GDAP1 is pathogenic (PMID: 34476298, PMID: 30373780, PMID: 34169998, PMID: 12499475, ClinVar SCV002059082.1). This variant has also been reported in ClinVar (Variation ID: 406136) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 263 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GDAP1 gene is an established disease mechanism in autosomal recessive Charcot-Marie-Tooth disease type 4A. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease type 4A. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3, PP1_Strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000406136, PMID:12499475). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	The c.786delG variant in the GDAP1 gene has been reported previously in the homozygous state in multiple affected siblings from two unrelated families segregating an autosomal recessive form of Charcot-Marie-Tooth syndrome; all tested family members who were heterozygous for the c.786delG variant were unaffected (Nelis et al., 2002). The c.786delG variant causes a frameshift starting with codon Phenylalanine 263, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Phe263LeufsX22. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.786delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.786delG as a likely pathogenic variant; however, the possibility it may be a rare benign variant cannot be completely excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -

Charcot-Marie-Tooth disease Uncertain:2

Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs1060500978; hg19: chr8-75276307;