ClinVar Miner

Submissions for variant NM_024818.6(UBA5):c.169A>G (p.Met57Val)

gnomAD frequency: 0.00001  dbSNP: rs532178791
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000255216 SCV001524930 uncertain significance Developmental and epileptic encephalopathy, 44 2020-02-07 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp RCV001859492 SCV002135716 uncertain significance not provided 2022-08-10 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 57 of the UBA5 protein (p.Met57Val). This variant is present in population databases (rs532178791, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of UBA5-related conditions (PMID: 27545681). ClinVar contains an entry for this variant (Variation ID: 265755). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects UBA5 function (PMID: 27545681, 29663568). 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.
GeneDx RCV001859492 SCV002538699 likely pathogenic not provided 2024-09-09 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: drastic reductions in catalytic activities and decreased ATP binding (PMID: 27545681, 38079206); 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: 27926783, 30078785, 36932998, 35672414, 27545681, 36680403, 38079206)
3billion RCV000255216 SCV002573339 pathogenic Developmental and epileptic encephalopathy, 44 2022-09-01 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: 0.009%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27545681 , 27545681 , 27926783). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90). The variant has been previously reported to be associated with UBA5-related disorder (PMID: 27545681). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27545681 , 27926783). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000255216 SCV000322723 pathogenic Developmental and epileptic encephalopathy, 44 2020-11-10 no assertion criteria provided literature only

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