VCV000265745.63 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic/Pathogenic, low penetrance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 265745 Accession: VCV000265745.63

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q22.1 3: 132675903 (GRCh38) [ NCBI UCSC ] 3: 132394747 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 9, 2016	Nov 17, 2024	Jun 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024818.6:c.1111G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079094.1:p.Ala371Thr	missense
NM_001320210.2:c.943G>A	NP_001307139.1:p.Ala315Thr	missense
NM_001321238.2:c.841G>A	NP_001308167.1:p.Ala281Thr	missense
NM_001321239.1:c.775G>A	NP_001308168.1:p.Ala259Thr	missense
NM_198329.4:c.943G>A	NP_938143.1:p.Ala315Thr	missense
NC_000003.12:g.132675903G>A
NC_000003.11:g.132394747G>A
NG_052968.1:g.26458G>A
	Q9GZZ9:p.Ala371Thr

... more HGVS ... less HGVS

Protein change

A371T, A315T, A259T, A281T

Other names

Canonical SPDI

NC_000003.12:132675902:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00109

Trans-Omics for Precision Medicine (TOPMed) 0.00139

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00154

The Genome Aggregation Database (gnomAD) 0.00169

Links

ClinGen: CA2621540 UniProtKB: Q9GZZ9#VAR_077158 OMIM: 610552.0001 dbSNP: rs114925667 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NPHP3-ACAD11	-	-	-	GRCh38	-	1474
UBA5		-	-	GRCh38 GRCh37	2	265

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Developmental and epileptic encephalopathy, 44	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000256081.17
not provided	Pathogenic/Pathogenic, low penetrance (8)	criteria provided, multiple submitters, no conflicts	Jun 14, 2024	RCV000523326.43
Developmental and epileptic encephalopathy, 44 Spinocerebellar ataxia, autosomal recessive 24	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 5, 2023	RCV000626058.12
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Dec 6, 2018	RCV000825503.8
UBA5-related disorder	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 14, 2023	RCV003323484.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Developmental and epileptic encephalopathy, 44 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: Broad Institute Center for Mendelian Genomics (CMG) Accession: SCV000786704.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (2) PubMed: 27545681‚ 27545674 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Ethnicity/Population group: Unspecified
Pathogenic (Dec 06, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Early infantile epileptic encephalopathy (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966807.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (4) PubMed: 27545674‚ 27545681‚ 27926783‚ 28965491 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 2
Pathogenic (May 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 44 Spinocerebellar ataxia, autosomal recessive 24 Our patient exhibits symptoms from (more...) (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Undiagnosed Diseases Network, NIH Accession: SCV000746680.3 First in ClinVar: Apr 29, 2018 Last updated: Mar 31, 2019	Comment: This variant has been described in multiple other cases in the literature and has been shown to be hypomorphic. Number of individuals with the variant: 1 Clinical Features: Ventouse delivery (present) , Truncal ataxia (present) , Telecanthus (present) , Spasticity (present) , Plagiocephaly (present) , Parkinsonism with favorable response to dopaminergic medication (present) … (more) Ventouse delivery (present) , Truncal ataxia (present) , Telecanthus (present) , Spasticity (present) , Plagiocephaly (present) , Parkinsonism with favorable response to dopaminergic medication (present) , Nystagmus (present) , Microcephaly (present) , Lower limb asymmetry (present) , Induced vaginal delivery (present) , Global developmental delay (present) , Failure to thrive (present) , Expressive language delay (present) , Esotropia (present) , Eczema (present) , Dystonia (present) , Difficulty walking (present) , Delayed speech and language development (present) , Deeply set eye (present) , Congenital muscular torticollis (present) , Chronic constipation (present) , Chorea (present) , Amblyopia (present) , Abnormal muscle tone (present) , Abnormal delivery (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: White Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2017-04-20 Testing laboratory interpretation: Likely pathogenic
Pathogenic (Feb 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 44 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Accession: SCV000746629.3 First in ClinVar: Oct 09, 2016 Last updated: Apr 28, 2021	Publications: PubMed (1) PubMed: 33811063 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Clinical Features: Underdeveloped nasolabial fold (present) , Tented upper lip vermilion (present) , Tapered finger (present) , Soft, doughy skin (present) , Short stature (present) , Sacral … (more) Underdeveloped nasolabial fold (present) , Tented upper lip vermilion (present) , Tapered finger (present) , Soft, doughy skin (present) , Short stature (present) , Sacral dimple (present) , Profound global developmental delay (present) , Posteriorly rotated ears (present) , Poor head control (present) , Oral-pharyngeal dysphagia (present) , Axial hypotonia (present) , Limb hypertonia (present) , Irritability (present) , Inversion of nipple (present) , Infantile encephalopathy (present) , Inability to walk (present) , Hypoplasia of the corpus callosum (present) , Horizontal nystagmus (present) , Hirsutism (present) , Heat intolerance (present) , Gastroesophageal reflux (present) , Failure to thrive (present) , Exotropia (present) , Exaggerated startle response (present) , EEG abnormality (present) , Dystonic disorder (present) , Delayed eruption of teeth (present) , Delayed CNS myelination (present) , Cutis marmorata (present) , Cerebral visual impairment (present) , Cerebral white matter atrophy (present) , Caesarian section (present) , Breech presentation (present) , Absent speech (present) , Abnormal cerebral white matter morphology (present) , Abnormal cerebral ventricle morphology (present) , Abnormal subcutaneous fat tissue distribution (present) , Abnormal conjugate eye movement (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: White Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2017-02-15 Testing laboratory interpretation: Pathogenic
Pathogenic (Jan 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 44 Spinocerebellar ataxia, autosomal recessive 24 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893633.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic, low penetrance (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001206482.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 27545674‚ 27545681‚ 28965491‚ 29286531 Comment: 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). … (more) 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 or hemizygous 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). (less)
Pathogenic (Jun 14, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000616912.7 First in ClinVar: Dec 19, 2017 Last updated: Sep 16, 2024	Comment: 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, … (more) 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) (less)
Pathogenic (Jan 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064444.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Developmental and epileptic encephalopathy, 44 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519930.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jul 14, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	UBA5-Related Disorders Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029717.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (2) PubMed: 27545681‚ 27545674 Comment: 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 … (more) 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. (less)
Likely pathogenic (Jun 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	UBA5-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104025.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (May 05, 2023)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Spinocerebellar ataxia, autosomal recessive 24 Developmental and epileptic encephalopathy, 44 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: inherited	New York Genome Center Accession: SCV004176039.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Clinical Features: Generalized myoclonic seizure (present) , Bilateral tonic-clonic seizure (present) , Gait disturbance (present) Secondary finding: no
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021585.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 44 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV003922011.2 First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 27545674‚ 27545681 Comment: 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 … (more) 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 (less)
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001962526.20 First in ClinVar: Oct 07, 2021 Last updated: Oct 20, 2024	Comment: UBA5: PM3:Very Strong, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 5
Pathogenic (Apr 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 44 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397468.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (5) PubMed: 33811063‚ 28965491‚ 27545674‚ 27545681‚ 29286531 Comment: 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 … (more) 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 (less)
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Epileptic encephalopathy, early infantile, 44 Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142330.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: 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 … (more) 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. (less)
Pathogenic (Nov 19, 2020)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 44 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000322713.2 First in ClinVar: Oct 09, 2016 Last updated: Nov 14, 2020	Publications: PubMed (2) PubMed: 27545674‚ 27545681 Comment on evidence: In 8 patients from 5 unrelated families of Finnish or European descent with developmental and epileptic encephalopathy-44 (DEE44; 617132), Muona et al. (2016) biallelic mutations … (more) In 8 patients from 5 unrelated families of Finnish or European descent with developmental and epileptic encephalopathy-44 (DEE44; 617132), Muona et al. (2016) biallelic mutations in the UBA5 gene. All patients carried a heterozygous a c.1111G-A transition (rs114925667) in exon 11, resulting in an ala371-to-thr (A371T) substitution at a highly conserved residue, on 1 allele. In the ExAC database, the A371T variant has an overall allele frequency of 0.19%, with 0.28% in non-Finnish Europeans, and 0.46% in Finnish individuals: no homozygotes were identified. The other pathogenic allele differed for each family: family A had a c.164G-A transition in exon 2, resulting in an arg55-to-his (R55H; 610552.0002) substitution at a highly conserved residue, family B had a c.855C-A transversion in exon 9, resulting in a tyr285-to-ter (Y285X; 610552.0003) substitution, family D had a c.181C-T transition in exon 2, resulting in an arg61-to-ter (R61X; 610552.0004) substitution, and families C and E families had a c.562C-T transition in exon 6, resulting in an arg188-to-ter (R188X; 610552.0005) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. The variants were filtered against the 1000 Genomes Project (phase 3 release), Exome Sequencing Project (v.0.025), and ExAC (v.0.3) databases. The R55H variant was found once in ExAC (8.29 x 10(-6)) and R188X was found twice in the Exome Variant Server in the heterozygous state, whereas R61X and Y285X were not found in the databases. Fibroblasts from patients from families A and B had decreased amounts of UBA5 mRNA and protein levels: the c.164G-A transition resulted in aberrant splicing and nonsense-mediated mRNA decay. Patient fibroblasts also showed decreased levels of UFM1 (610553)-UBA5 and UFM1-UBA1 (314370) intermediates. In vitro functional expression assays in HEK293 cells showed that the A371T and R55H missense mutations resulted in impaired formation of UFM1-UBA5 intermediates, consistent with a decrease in E1-like activity and an attenuated ability to transfer activated UFM1 to UFC1 (610554) compared to wildtype. The A371T variant had about 70 to 80% residual activity, and the R55H variant had about 50% residual activity, indicating a hypomorphic effect. The patients had onset of refractory infantile spasms in the first weeks or months of life. Colin et al. (2016) identified compound heterozygosity for the A371T variant and another pathogenic mutation in the UBA5 gene (see 610552.0006 and 610552.0007) in 3 children from 2 unrelated families of European origin with DEE44. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797447.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967687.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034091.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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 or hemizygous 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).

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy.	Briere LC	Cold Spring Harbor molecular case studies	2021	PMID: 33811063
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.	Tumienė B	Clinical genetics	2018	PMID: 29286531
Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.	Arnadottir GA	BMC medical genetics	2017	PMID: 28965491
A novel approach to assess the ubiquitin-fold modifier 1-system in cells.	Ishimura R	FEBS letters	2017	PMID: 27926783
Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy.	Colin E	American journal of human genetics	2016	PMID: 27545681
Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.	Muona M	American journal of human genetics	2016	PMID: 27545674

Text-mined citations for rs114925667 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs114925667 ...