Submissions for variant NM_000817.3(GAD1):c.1252G>T (p.Val418Phe)

dbSNP: rs143058194

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001836790	SCV000419237	uncertain significance	Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	2018-01-12	criteria provided, single submitter	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.
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000515943	SCV000574481	uncertain significance	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001836790	SCV001418592	uncertain significance	Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	2021-08-31	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV003437057	SCV004150095	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	GAD1: BP4
Ambry Genetics	RCV004021779	SCV004873646	uncertain significance	Inborn genetic diseases	2024-02-07	criteria provided, single submitter	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.
Breakthrough Genomics, Breakthrough Genomics	RCV003437057	SCV005188040	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003957711	SCV004770519	likely benign	GAD1-related disorder	2022-05-18	no assertion criteria provided	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).