Submissions for variant NM_001008216.2(GALE):c.151C>T (p.Arg51Trp)

gnomAD frequency: 0.00002  dbSNP: rs780517804

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265572	SCV001443734	likely pathogenic	UDPglucose-4-epimerase deficiency	2019-11-11	criteria provided, single submitter	clinical testing	This variant has been previously reported as a homozygous change in multiple affected individuals from the same kindred with histories of thrombocytopenia, intracranial bleeding, anemia, and febrile neutropenia (PMID: 30247636). The variant segregated with disease in this kindred. Functional characterization of the variant protein demonstrated significantly lower enzymatic activity and greatly increased thermal instability (PMID: 30247636). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/245814) and thus is presumed to be rare. The c.151C>T (p.Arg51Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.151C>T (p.Arg51Trp) variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001265572	SCV001569152	pathogenic	UDPglucose-4-epimerase deficiency	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 51 of the GALE protein (p.Arg51Trp). This variant is present in population databases (rs780517804, gnomAD 0.02%). This missense change has been observed in individual(s) with GALE-related conditions and/or thrombocytopenia (PMID: 30247636, 33510604). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 984932). 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. Experimental studies have shown that this missense change affects GALE function (PMID: 30247636). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002307717	SCV002601325	uncertain significance	not provided	2022-05-17	criteria provided, single submitter	clinical testing	Observed as homozygous and segregating in a family with multiple individuals with severe thrombocytopenia, mild anemia, and febrile neutropenia in in the published literature (Seo et al., 2019) and as homozygous in a patient with thrombocytopenia, leukopenia, and immunodeficiency previously tested at GeneDx; Observed as in trans with a second GALE variant in a patient with pancytopenia, congenital heart defects, bone marrow dysfunction, and GALE deficiency without classic features of galactosemia in published literature (Febres-Aldana et al., 2020); Published functional studies demonstrate a damaging effect with reduced enzyme activity and thermal instability (Seo et al., 2019); This variant is associated with the following publications: (PMID: 32350996, 30247636, 33510604)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001265572	SCV003924283	likely pathogenic	UDPglucose-4-epimerase deficiency	2023-05-08	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005014318	SCV005647058	likely pathogenic	UDPglucose-4-epimerase deficiency; Thrombocytopenia 13, syndromic	2024-01-24	criteria provided, single submitter	clinical testing
GeneReviews	RCV001265572	SCV002014562	not provided	UDPglucose-4-epimerase deficiency		no assertion provided	literature only	Segregated with thrombocytopenia in a consanguineous family
OMIM	RCV003994248	SCV004809174	pathogenic	Thrombocytopenia 13, syndromic	2024-04-05	no assertion criteria provided	literature only