rs1060500979

Positions:

• chr8-74361975-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018972.4(GDAP1):​c.579del​(p.Lys193AsnfsTer13) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000711 in 1,407,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GDAP1 NM_018972.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 6.76

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-74361975-TA-T is Pathogenic according to our data. Variant chr8-74361975-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 406137.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4	c.579del	p.Lys193AsnfsTer13	frameshift_variant, splice_region_variant	4/6	ENST00000220822.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDAP1	ENST00000220822.12	c.579del	p.Lys193AsnfsTer13	frameshift_variant, splice_region_variant	4/6	1	NM_018972.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407094 Hom.: 0 Cov.: 24 AF XY: 0.00000142 AC XY: 1 AN XY: 703374

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

This sequence change creates a premature translational stop signal (p.Lys193Asnfs*13) in the GDAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GDAP1 are known to be pathogenic (PMID: 11743580). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 406137). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

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

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jan 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1060500979; hg19: chr8-75274210;