NM_024818.6(UBA5):c.169A>G (p.Met57Val) AND Developmental and epileptic encephalopathy, 44

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 1, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255216.6

Allele description [Variation Report for NM_024818.6(UBA5):c.169A>G (p.Met57Val)]

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

Genes:

NPHP3-ACAD11:NPHP3-ACAD11 readthrough (NMD candidate) [Gene - HGNC]
UBA5:ubiquitin like modifier activating enzyme 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q22.1

Genomic location:

Preferred name:

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

HGVS:

NC_000003.12:g.132665830A>G
NG_052968.1:g.16385A>G
NM_001320210.2:c.1A>G
NM_001321238.2:c.28-2988A>G
NM_001321239.1:c.-39-2988A>G
NM_024818.6:c.169A>GMANE SELECT
NM_198329.4:c.1A>G
NP_001307139.1:p.Met1Val
NP_079094.1:p.Met57Val
NP_079094.1:p.Met57Val
NP_938143.1:p.Met1Val
NC_000003.11:g.132384674A>G
NM_024818.3:c.169A>G
NM_024818.4:c.169A>G
Q9GZZ9:p.Met57Val

Protein change:

M1V; MET57VAL

Links:

UniProtKB: Q9GZZ9#VAR_077154; OMIM: 610552.0010; dbSNP: rs532178791

NCBI 1000 Genomes Browser:

rs532178791

Molecular consequence:

NM_001320210.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_198329.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001321238.2:c.28-2988A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001321239.1:c.-39-2988A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001320210.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024818.6:c.169A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198329.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 44 (DEE44)
Synonyms:: Epileptic encephalopathy, early infantile, 44
Identifiers:: MONDO: MONDO:0014933; MedGen: C4310700; OMIM: 617132

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322723	OMIM	no assertion criteria provided	Pathogenic (Nov 10, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001524930	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 7, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002573339	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27545681, 27926783, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322723

OMIM

no assertion criteria provided

Pathogenic
(Nov 10, 2020)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001524930

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 7, 2020)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002573339

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy.

Colin E, Daniel J, Ziegler A, Wakim J, Scrivo A, Haack TB, Khiati S, Denommé AS, Amati-Bonneau P, Charif M, Procaccio V, Reynier P, Aleck KA, Botto LD, Herper CL, Kaiser CS, Nabbout R, N'Guyen S, Mora-Lorca JA, Assmann B, Christ S, Meitinger T, et al.

Am J Hum Genet. 2016 Sep 1;99(3):695-703. doi: 10.1016/j.ajhg.2016.06.030. Epub 2016 Aug 18.

PubMed [citation]

PMID:: 27545681
PMCID:: PMC5011045

A novel approach to assess the ubiquitin-fold modifier 1-system in cells.

Ishimura R, Obata M, Kageyama S, Daniel J, Tanaka K, Komatsu M.

FEBS Lett. 2017 Jan;591(1):196-204. doi: 10.1002/1873-3468.12518. Epub 2016 Dec 20.

PubMed [citation]

PMID:: 27926783

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000322723.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 6-year-old girl, born of unrelated parents from Kuwait (family D), with developmental and epileptic encephalopathy-44 (DEE44; 617132), Colin et al. (2016) identified compound heterozygous mutations in the UBA5 gene: a c.169A-G transition (c.169A-G, NM_024818) in exon 2, resulting in a met57-to-val (M57V) substitution, and a c.503G-A transition in exon 6, resulting in a gly168-to-glu (G168E; 610552.0011) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues. The c.169A-G variant was found in the ExAC database at a low frequency (8.3 x 10(-5)). In vitro functional expression studies showed that the G168E mutant protein was catalytically inactive, whereas M57V caused a drastic reduction in catalytic activity. Although the patient had early-onset encephalopathy with microcephaly, hypotonia, abnormal movements, and intellectual disability, she did not have overt epilepsy. Colin et al. (2016) postulated that the missense mutations in this patient may have conferred a less severe phenotype than did truncating mutations.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001524930.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002573339.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine