rs756461496
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_018972.4(GDAP1):c.1019dup(p.Arg341GlnfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
GDAP1
NM_018972.4 frameshift
NM_018972.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.08
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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. Fraction of 0.0576 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 8-74364305-C-CT is Pathogenic according to our data. Variant chr8-74364305-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GDAP1 | NM_018972.4 | c.1019dup | p.Arg341GlnfsTer12 | frameshift_variant | 6/6 | ENST00000220822.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GDAP1 | ENST00000220822.12 | c.1019dup | p.Arg341GlnfsTer12 | frameshift_variant | 6/6 | 1 | NM_018972.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251430Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461796Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727216
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 2022 | The c.1019dupT variant, located in coding exon 6 of the GDAP1 gene, results from a duplication of T at nucleotide position 1019, causing a translational frameshift with a predicted alternate stop codon (p.R341Qfs*12). This alteration occurs at the 3' terminus of the GDAP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 3% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is expected to be causative of a spectrum of autosomal recessive Charcot-Marie-Tooth (CMT) diseases including CMT recessive intermediate type A (CMTRIA), axonal CMT disease with vocal cord paresis, and CMT type 4A (CMT4A) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant axonal CMT disease, type 2K (CMT2K) is unclear. - |
Charcot-Marie-Tooth disease type 4A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 02, 2023 | This premature translational stop signal has been observed in individual(s) with autosomal recessive neuropathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant neuropathy (PMID: 25614874; Invitae); however, the role of the variant in this condition is currently unclear. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 406140). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg341Glnfs*12) in the GDAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the GDAP1 protein. - |
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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at