rs104894080

chr8-74364005-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_018972.4(GDAP1):c.715C>T(p.Leu239Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,613,944 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L239H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:3 O:1
• Conservation: PhyloP100: 3.69

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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr8-74364006-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1709478.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 8-74364005-C-T is Pathogenic according to our data. Variant chr8-74364005-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-74364005-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDAP1	NM_018972.4	c.715C>T	p.Leu239Phe	missense_variant	6/6	ENST00000220822.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDAP1	ENST00000220822.12	c.715C>T	p.Leu239Phe	missense_variant	6/6	1	NM_018972.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251444 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42 AN XY: 727200

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: 0.0000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000996 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was detected in homozygous state. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 239 of the GDAP1 protein (p.Leu239Phe). This variant is present in population databases (rs104894080, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 14561495, 17433678, 18504680, 18991200, 19500985, 20232219, 25231362). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 20232219). ClinVar contains an entry for this variant (Variation ID: 4200). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	Published functional studies demonstrate that the variant results in protein mislocalization (Rzepnikowska et al., (2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18991200, 14561495, 17433678, 18504680, 20232219, 19500985, 17039978, 27549087, 29372391, 29858556, 32183277, 33477664, 31589614, 20685671, 20849849, 23628762, 32376792) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GDAP1: PM3:Very Strong, PP1:Strong, PM1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with autosomal recessive Charcot-Marie-Tooth disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

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

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Oct 03, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Mar 01, 2022	- -

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

Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

Sensory neuropathy;C0152025:Polyneuropathy;C0241005:Elevated circulating creatine kinase concentration;C1263857:Peripheral axonal neuropathy;C1314665:Elevated circulating alkaline phosphatase concentration Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 02, 2015

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.715C>T (p.L239F) alteration is located in exon 6 (coding exon 6) of the GDAP1 gene. This alteration results from a C to T substitution at nucleotide position 715, causing the leucine (L) at amino acid position 239 to be replaced by a phenylalanine (F). Based on the available evidence, the GDAP1 c.715C>T (p.L239F) alteration is classified as pathogenic for autosomal recessive GDAP1-related Charcot-Marie-Tooth disease; however, it is unlikely to be causative of autosomal dominant GDAP1-related Charcot-Marie-Tooth disease, type 2. Based on data from gnomAD, the T allele has an overall frequency of 0.004% (10/282836) total alleles studied. The highest observed frequency was 0.008% (10/129150) of European (non-Finnish) alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in GDAP1 in multiple individuals with autosomal recessive GDAP1-related Charcot-Marie-Tooth disease (Kabziska, 2010; Barankova, 2007; Moroni, 2009; Rougeot, 2008; Auer-Grumbach, 2008; Kabziska, 2014). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest this variant disrupts mitochondrial and golgi function in yeast and human cells; however, the physiological relevance of these findings is unclear (Rzepnikowska, 2020; Binida, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

GDAP1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 20, 2018

The GDAP1 c.715C>T (p.Leu239Phe) missense variant has been reported in at least six studies and is found in a total of 21 probands with autosomal recessive Charcot-Marie-Tooth disease (CMT), including five in a homozygous state, 15 in a compound heterozygous state, and one in a heterozygous state without a second variant identified (Ammar et al. 2003, Kabzinska et al. 2003, Barankova et al. 2007, Auer-Grumbach et al. 2008, Moroni et al. 2009, Kabzinska et al. 2010). Ammar et al. (2003) identified the c.715C>T (p.Leu239Phe) variant in a compound heterozygous state with a frameshift variant in two siblings with CMT. Their unaffected mother carried the p.Leu239Phe variant and their unaffected father carried the frameshift variant. The p.Leu239Phe variant was absent from 158 controls and is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. Haplotype analysis suggests that the p.Leu239Phe variant is likely a founder mutation in the central and eastern European population (Kabzinska et al. 2010). Based on the collective evidence, the p.Leu239Phe variant classified as pathogenic for GDAP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Charcot-Marie-Tooth disease recessive intermediate A;C1842983:Charcot-Marie-Tooth disease axonal type 2K;C1843183:Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive;C1859198:Charcot-Marie-Tooth disease type 4A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MVP		0.97
MPC		1.4
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894080; hg19: chr8-75276240; COSMIC: COSV55187285; COSMIC: COSV55187285;