rs756121249

Variant names:

• chr8-74350570-T-A
• rs756121249
• NM_018972.4:c.109T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PP2 PP3_Strong PP5

The NM_018972.4(GDAP1):​c.109T>A​(p.Ser37Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,434,190 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S37S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.31
• Publications: 1 publications found

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]

GDAP1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2K

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease recessive intermediate A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant Charcot-Marie-Tooth disease type 2K

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 4A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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, 12 uncertain in NM_018972.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0 (below the threshold of 3.09). Trascript score misZ: 1.1646 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease recessive intermediate A, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, autosomal dominant Charcot-Marie-Tooth disease type 2K.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 8-74350570-T-A is Pathogenic according to our data. Variant chr8-74350570-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426898.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDAP1	NM_018972.4	c.109T>A	p.Ser37Thr	missense_variant	Exon 1 of 6	ENST00000220822.12	NP_061845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDAP1	ENST00000220822.12	c.109T>A	p.Ser37Thr	missense_variant	Exon 1 of 6	1	NM_018972.4	ENSP00000220822.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251336 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1434190 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 715138

African (AFR) AF: 0.00 AC: 0 AN: 32898

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000644 AC: 7 AN: 1086838

Other (OTH) AF: 0.00 AC: 0 AN: 59440

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Mar 28, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant that is likely pathogenic has been identified in the GDAP1 gene. The S37T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S37T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a conserved position predicted to be within the GST N-terminal domain. Missense variants at other residues in the GST domain have been reported in Human Gene Mutation Database in association with GDAP1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the S37T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Inborn genetic diseases Uncertain:1

Oct 07, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 37 of the GDAP1 protein (p.Ser37Thr). This variant is present in population databases (rs756121249, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GDAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426898). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.85		Loss of MoRF binding (P = 0.1316);
MVP		0.73
MPC		1.1
ClinPred		0.98	D
GERP RS		5.1
PromoterAI		-0.073	Neutral
Varity_R		0.74
gMVP		0.91
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs756121249; hg19: chr8-75262805;