NM_018972.4:c.653A>C

Variant names:

• chr8-74363012-A-C
• rs556827873
• NM_018972.4:c.653A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_018972.4(GDAP1):​c.653A>C​(p.Gln218Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,180 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q218E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GDAP1 NM_018972.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.89
• Publications: 0 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-74363011-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4201.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 recessive intermediate A, Charcot-Marie-Tooth disease axonal type 2K, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4A.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	NM_018972.4	MANE Select	c.653A>C	p.Gln218Pro	missense	Exon 5 of 6	NP_061845.2	Q8TB36-1
	GDAP1	NM_001362930.2		c.479A>C	p.Gln160Pro	missense	Exon 4 of 5	NP_001349859.1	A0A6Q8PEZ4
	GDAP1	NM_001040875.4		c.449A>C	p.Gln150Pro	missense	Exon 5 of 6	NP_001035808.1	Q8TB36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.653A>C	p.Gln218Pro	missense	Exon 5 of 6	ENSP00000220822.7	Q8TB36-1
	GDAP1	ENST00000434412.3	TSL:1	c.521A>C	p.Gln174Pro	missense	Exon 6 of 7	ENSP00000417006.3	A0A7I2RYU0
	GDAP1	ENST00000675463.1		c.653A>C	p.Gln218Pro	missense	Exon 5 of 7	ENSP00000502327.1	A0A6Q8PGS2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428180 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 712908

African (AFR) AF: 0.00 AC: 0 AN: 32798

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 85538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081464

Other (OTH) AF: 0.0000169 AC: 1 AN: 59214

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 4A (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.65		Loss of helix (P = 0.0104)
MVP		0.99
MPC		1.4
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.92
Mutation Taster		=8/92	disease causing

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: rs556827873; hg19: chr8-75275247;