Submissions for variant NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)

gnomAD frequency: 0.00169  dbSNP: rs114925667

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523326	SCV000616912	pathogenic	not provided	2024-06-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a slightly reduced activity on UFM1 activation with an attenuated ability to transfer the activated UFM1 to UFC1 (PMID: 27545674, 27545681, 27926783); 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: 30287594, 27545681, 27545674, 27926783, 28965491, 2179706, 32149490, 31980526, 34426522, 34299007, 33811063, 33726816, 34588452, 38079206, 36680403, 37947621, 38328212, 37432431, 37838930, 37945409)
Undiagnosed Diseases Network, NIH	RCV000256081	SCV000746629	pathogenic	Developmental and epileptic encephalopathy, 44	2017-02-15	criteria provided, single submitter	clinical testing	A heterozygous c.1111G>A (p.A371T) pathogenic variant in the UBA5 gene was detected in this individual. This variant in compound heterozygosity with another pathogenic variant has been previously reported as disease causing in multiple unrelated patients affected with early infantile epileptic encephalopathy [PMID 27545681, 27545681]. This variant in homozygous state has also been previously reported in one individual who is free of any neurological disorder in his fifties. In combination with data from in vitro functional studies, the c.1111G>A (p.A371T) variant was suggested to act as a hypomorphic allele [PMID 27545681]. ACMG criteria applied: PS1, PS3, PM2, PM3, PP3, PP4, BS2.
Undiagnosed Diseases Network, NIH	RCV000626058	SCV000746680	pathogenic	Developmental and epileptic encephalopathy, 44; Spinocerebellar ataxia, autosomal recessive 24	2018-05-21	criteria provided, single submitter	clinical testing	This variant has been described in multiple other cases in the literature and has been shown to be hypomorphic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000256081	SCV000786704	pathogenic	Developmental and epileptic encephalopathy, 44		criteria provided, single submitter	research	The heterozygous p.Ala371Thr variant was identified in the compound heterozygous state by our study in one individual with Epileptic Encephalopathy. The p.Ala371Thr variant has been reported in the literature in 11 individuals across 7 families (Colin 2016, Muona 2016). Of note, all of these individuals were compound heterozygous with a loss-of-function variant. This variant has been identified in 0.58% (148/25672, no homozygotes) of Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs114925667). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000626058	SCV000893633	pathogenic	Developmental and epileptic encephalopathy, 44; Spinocerebellar ataxia, autosomal recessive 24	2022-01-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825503	SCV000966807	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2018-12-06	criteria provided, single submitter	clinical testing	The p.Ala371Thr variant in UBA5 has been reported in a compound heterozygous sta te with a loss-of-function variant in 6 probands with early infantile epileptic encephalopathy and segregated with disease in 4 additional affected relatives (M uona 2016, Colin 2016). Two additional probands and one additional sib have been identified with either missense or silent with suspected splice effects in tran s with this variant (Muona 2016, Arnadottir 2017). While several homozygous indi viduals without neurological symptoms into adulthood have been reported in the l iterature (Colin 2016, Arnadottir 2017), functional assays demonstrating an inte rmediate enzyme activity compared to loss-of-function variants and controls supp ort the conclusion that this variant is a hypomorphic allele with a low risk of phenotypic effect in a homozygous state (Muona 2016, Colin 2016). In summary, th is variant meets criteria to be classified as pathogenic for early infantile epi leptic encephalopathyin an autosomal recessive manner based upon case counts, se gregation studies, and functional evidence. ACMG/AMP Criteria applied: PM3_VeryS trong, PP1_Moderate, PS3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523326	SCV001206482	pathogenic, low penetrance	not provided	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 371 of the UBA5 protein (p.Ala371Thr). This variant is present in population databases (rs114925667, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with UBA5-related epileptic encephalopathy (PMID: 27545674, 27545681, 28965491, 29286531). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This missense change has been observed to be homozygous, hemizygous or homoplasmic in an individual who did not have the expected clinical features for that genetic result (PMID: 27545681, 28965491). ClinVar contains an entry for this variant (Variation ID: 265745). 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 UBA5 function (PMID: 27545674, 27545681). In summary, this variant has been reported as a hypomorphic variant that partially decreases UBA5 protein function. This variant causes UBA5-related epileptic encephalopathy when in trans from a null variant; however, homozygous individuals appear to be clinically unaffected. For these reasons, this variant has been classified as Pathogenic (low penetrance).
CeGaT Center for Human Genetics Tuebingen	RCV000523326	SCV001962526	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	UBA5: PM3:Very Strong, PM2:Supporting, PS3:Supporting
Revvity Omics, Revvity	RCV000523326	SCV002021585	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000523326	SCV002064444	pathogenic	not provided	2019-01-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000256081	SCV002519930	pathogenic	Developmental and epileptic encephalopathy, 44	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000256081	SCV003922011	pathogenic	Developmental and epileptic encephalopathy, 44	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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 44 (MIM#617132). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (244 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transthiolation domain (PMID: 27545674). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and is consistently reported in compound heterozygous patients with early-onset epileptic encephalopathy, where homozygous individuals are not affected (ClinVar, Decipher, PMID: 27545681, PMID: 27545674). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been functionally established as a hypomorphic allele, resulting in a modest reduction in enzyme activity (PMID: 27545681, PMID: 27545674). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323484	SCV004029717	pathogenic	UBA5-related disorder	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: UBA5 c.1111G>A (p.Ala371Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 243374 control chromosomes, predominately at a frequency of 0.0059 in the Finnish European subpopulation in the gnomAD database. However, it has been reported as a hypomorphic allele, expected to result in disease only when found in trans with a pathogenic variant (e.g. Colin_2016, Muona_2016). Indeed, c.1111G>A has been reported in the literature in the compound heterozygous state in trans with a pathogenic variant in multiple individuals affected with Early Onset Encephalopathy from at least seven different families and has been found to segregate with disease (e.g. Colin_2016, Muona_2016). It has also been identified in a homozygous individual who was unaffected, having no reported neurological symptoms at over 50 years of age (Muona_2016). These data indicate that the variant is very likely to be a hypomorphic allele associated with disease. Experimental studies evaluating an impact on protein function found that the variant results in decreased E1 activity compared to the wild-type protein, but retains the ability to form the intermmediate between UFC1 and UFM1, although at a slower reaction rate, further supporting that the variant functions as a hypomorphic allele (e.g. Colin_2016, Muona_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27545681, 27545674). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=12)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003323484	SCV004104025	likely pathogenic	UBA5-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The UBA5 c.1111G>A variant is predicted to result in the amino acid substitution p.Ala371Thr. This variant has been reported in the compound heterozygous state, segregating with autosomal recessive early infantile epileptic encephalopathy in several patients (Muona et al. 2016. PubMed ID: 27545674; Colin et al. 2016. PubMed ID: 27545681; Arnadottir et al. 2017. PubMed ID: 28965491; Tumienė et al. 2017. PubMed ID: 29286531). This variant was also reported in the homozygous state in three Icelandic individuals who had no signs of neurological disease, suggesting that p.Ala371Thr acts as a hypomorphic variant (Arnadottir et al 2017. PubMed ID: 28965491). This variant is interpreted as likely pathogenic.
New York Genome Center	RCV000626058	SCV004176039	pathogenic	Developmental and epileptic encephalopathy, 44; Spinocerebellar ataxia, autosomal recessive 24	2023-05-05	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000256081	SCV005397468	pathogenic	Developmental and epileptic encephalopathy, 44	2022-04-11	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid substitution at position 371 of the UBA5 protein. This is a previously reported variant (ClinVar) that is found in control population datasets (gnomAD database 517/274744 alleles or 0.18%) at a level consistent with carrier status for an Autosomal recessive inheritance disease. This variant is observed as a compound heterozygous variant in individuals with UBA5-related disease and segregates with affected family members (PMID: 29286531, 28965491, 27545674). Bioinformatic tools predict that this variant would be damaging and the Ala371 residue is highly conserved across the vertebrate species examined. Functiol alysis suggests that this is a hypomorphic allele in which the protein produced by this variant retains its interaction with UFM1 but reduces the trans-esterification of UFM1 to UFC1 (PMID: 27545681, 33811063). Consistent with this, individuals homozygous for this variant are reported to be uffected (PMID: 28965491). Because this variant is reported as compound heterozygous in affected individuals for a recessive disorder, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP1, PS3
OMIM	RCV000256081	SCV000322713	pathogenic	Developmental and epileptic encephalopathy, 44	2020-11-19	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000256081	SCV001142330	pathogenic	Developmental and epileptic encephalopathy, 44	2020-01-06	no assertion criteria provided	curation	NM_198329.2:c.943G>A in the UBA5 gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This variant also known as A371T in literature. This variant in compound heterozygosity with another pathogenic variant has been previously reported as disease causing in multiple unrelated patients affected with early infantile epileptic encephalopathy (PMID: 27545681). Functional studies of A371T indicate that it results in slightly reduced activity on UFM1 activation with an attenuated ability to transfer the activated UFM1 to UFC1 (PMID: 27545681, 27545674). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_Strong, PS3, PP3.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000523326	SCV001797447	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000523326	SCV001967687	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000523326	SCV002034091	pathogenic	not provided		no assertion criteria provided	clinical testing