Submissions for variant NM_000507.4(FBP1):c.841G>A (p.Glu281Lys)

dbSNP: rs566453434

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432051	SCV000520990	pathogenic	not provided	2023-07-04	criteria provided, single submitter	clinical testing	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: 27101822, 29774539, 29016355, 31584309, 23881342, 33083013, 26549536)
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000681449	SCV000808909	pathogenic	Fructose-biphosphatase deficiency	2012-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV000681449	SCV000936372	pathogenic	Fructose-biphosphatase deficiency	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 281 of the FBP1 protein (p.Glu281Lys). This variant is present in population databases (rs566453434, gnomAD 0.06%). This missense change has been observed in individuals with fructose-1,6-bisphosphatase deficiency (PMID: 23881342, 27101822, 29016355, 29774539; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBP1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000681449	SCV001424416	pathogenic	Fructose-biphosphatase deficiency		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000681449	SCV002023051	pathogenic	Fructose-biphosphatase deficiency	2021-04-09	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000681449	SCV002053768	likely pathogenic	Fructose-biphosphatase deficiency		criteria provided, single submitter	clinical testing
3billion	RCV000681449	SCV002521202	pathogenic	Fructose-biphosphatase deficiency	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000381580). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:23881342, 27101822, 29016355, 29774539). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000681449	SCV003836378	pathogenic	Fructose-biphosphatase deficiency	2022-03-06	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000681449	SCV003923325	likely pathogenic	Fructose-biphosphatase deficiency		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.841G>A in Exon 7 of the FBP1 gene that results in the amino acid substitution p.Glu281Lys was identified. The observed variant has a minor allele frequency of 0.00008% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic with 2 stars, criteria provided, multiple submitters, no conflicts (Variant ID: 381580). This variant has previously been reported for fructose-1,6-bisphosphatase deficiency by Santer R,et,al.,2016. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000681449	SCV004035248	pathogenic	Fructose-biphosphatase deficiency	2022-12-21	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000681449	SCV001469249	likely pathogenic	Fructose-biphosphatase deficiency	2020-10-11	no assertion criteria provided	clinical testing