2-170852781-G-T

Variant names:

• chr2-170852781-G-T
• rs143058194
• NM_000817.3:c.1252G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000817.3(GAD1):​c.1252G>T​(p.Val418Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,614,030 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V418I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: GAD1 NM_000817.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.75
• Publications: 4 publications found

Genes affected

GAD1 (HGNC:4092): (glutamate decarboxylase 1) This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

GAD1 Gene-Disease associations (from GenCC):

• early infantile epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 89

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cerebral palsy, spastic quadriplegic, 1

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19945809).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00101 (153/152204) while in subpopulation AMR AF = 0.0036 (55/15286). AF 95% confidence interval is 0.00284. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.1252G>T	p.Val418Phe	missense	Exon 13 of 17	NP_000808.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.1252G>T	p.Val418Phe	missense	Exon 13 of 17	ENSP00000350928.3
	GAD1	ENST00000488724.5	TSL:1	n.352G>T		non_coding_transcript_exon	Exon 2 of 6
	GAD1	ENST00000493875.5	TSL:1	n.*86G>T		non_coding_transcript_exon	Exon 13 of 17	ENSP00000434696.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.000541 AC: 136 AN: 251472 AF XY: 0.000589

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000423 AC: 619 AN: 1461826 Hom.: 2 Cov.: 30 AF XY: 0.000448 AC XY: 326 AN XY: 727232

African (AFR) AF: 0.00131 AC: 44 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53418

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.000297 AC: 330 AN: 1111952

Other (OTH) AF: 0.00118 AC: 71 AN: 60392

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152204 Hom.: 1 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74418

African (AFR) AF: 0.00106 AC: 44 AN: 41526

American (AMR) AF: 0.00360 AC: 55 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4818

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.0000280 Hom.: 0

Bravo AF: 0.00144

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000164

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with phenylalanine at codon 418 of the GAD1 protein (p.Val418Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs143058194, ExAC 0.08%). This missense change has been observed in individual(s) with GAD1-related disease (PMID: 28832565). ClinVar contains an entry for this variant (Variation ID: 332237). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

not provided Uncertain:1 Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAD1: BP4, BS2

Inborn genetic diseases Uncertain:1

Feb 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1252G>T (p.V418F) alteration is located in exon 13 (coding exon 12) of the GAD1 gene. This alteration results from a G to T substitution at nucleotide position 1252, causing the valine (V) at amino acid position 418 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Hereditary spastic paraplegia Uncertain:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

GAD1-related disorder Benign:1

May 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.26
Sift	Benign	0.39	T
Sift4G	Benign	0.34	T
Polyphen		0.98	D
Vest4		0.83
MVP		0.86
MPC		1.6
ClinPred		0.025	T
GERP RS		3.1
Varity_R		0.34
gMVP		0.94
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs143058194; hg19: chr2-171709291;