Submissions for variant NM_006759.4(UGP2):c.34A>G (p.Met12Val)

gnomAD frequency: 0.00001  dbSNP: rs768305634

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001370354	SCV001566825	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the UGP2 protein (p.Met12Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects UGP2 function (PMID: 31820119). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 805980). This missense change has been observed in individuals with clinical features of UGP2-related developmental and epileptic encephalopathy (PMID: 31820119; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs768305634, gnomAD 0.04%).
Undiagnosed Diseases Network, NIH	RCV000993844	SCV001827225	likely pathogenic	Developmental and epileptic encephalopathy, 83	2021-05-19	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002273831	SCV002558738	likely pathogenic	D-6618		criteria provided, single submitter	clinical testing	Homozygous missense variation in exon 2 of UGP2 gene that result in the amino acid substitution of caline for methionine at codon 21 was detected. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000993844	SCV002574742	pathogenic	Developmental and epileptic encephalopathy, 83	2022-06-30	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000993844	SCV002820275	pathogenic	Developmental and epileptic encephalopathy, 83		criteria provided, single submitter	clinical testing	The missense variant p.M12V in UGP2 (NM_006759.3) has been previously reported as a recurrent homozygous mutation in similarly affected patients (Perenthaler E et al). The variant causes a disruption of the start codon of the shorter isoform, which is predominant in brain and hence leads to disease as proved by functional studies on zebrafish (Perenthaler E et al). The p.M12V variant is observed in 12/30,282 (0.0396%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submiited to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000993844	SCV003921984	pathogenic	Developmental and epileptic encephalopathy, 83	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (15 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 22 individuals from 15 families (PMID: 31820119). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells and leads to altered glycogen metabolims (PMID: 31820119). (SP) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000993844	SCV004040721	pathogenic	Developmental and epileptic encephalopathy, 83	2023-03-29	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000993844	SCV004045777	pathogenic	Developmental and epileptic encephalopathy, 83	2023-10-19	criteria provided, single submitter	clinical testing	This homozygous start loss variant identified in 7 month female with refractory seizure, pneumonia, GDD with west syndrome. This nucleotide change has an allele frequency of 0.0053% in gnomAD aggregate database [PM2]. This variant has a clinvar entry with Pathogenic/Likely Pathogenic interpretation by multiple submitter [PP5]. Clinvar variation ID: 805980. PMID: 31820119. Based on available evidence the variant is classified as "Pathogenic".
OMIM	RCV000993844	SCV001147001	pathogenic	Developmental and epileptic encephalopathy, 83	2020-10-21	no assertion criteria provided	literature only