NM_006759.4(UGP2):c.34A>G (p.Met12Val) AND Developmental and epileptic encephalopathy, 83

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Oct 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000993844.15

Allele description [Variation Report for NM_006759.4(UGP2):c.34A>G (p.Met12Val)]

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

Gene:

UGP2:UDP-glucose pyrophosphorylase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p15

Genomic location:

Preferred name:

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

Other names:

p.Met12Val

HGVS:

NC_000002.12:g.63856320A>G
NM_001001521.2:c.1A>G
NM_001377524.1:c.1A>G
NM_001377525.1:c.1A>G
NM_001377526.1:c.-496A>G
NM_001377527.1:c.-106+15088A>G
NM_001377528.1:c.-415A>G
NM_001377529.1:c.-496A>G
NM_006759.4:c.34A>GMANE SELECT
NP_001001521.1:p.Met1Val
NP_001364453.1:p.Met1Val
NP_001364454.1:p.Met1Val
NP_006750.3:p.Met12Val
NP_006750.3:p.Met12Val
NC_000002.11:g.64083454A>G
NM_001001521.1:c.1A>G
NM_001001521.2:c.1A>G
NM_006759.3:c.34A>G
NM_006759.3:c.34A>G

Protein change:

M12V

Links:

OMIM: 191760.0001; dbSNP: rs768305634

NCBI 1000 Genomes Browser:

rs768305634

Molecular consequence:

NM_001377526.1:c.-496A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001377528.1:c.-415A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001377529.1:c.-496A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001001521.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001377524.1:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001377525.1:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001377527.1:c.-106+15088A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001001521.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377524.1:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377525.1:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006759.4:c.34A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 83
Synonyms:: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 83; BARAKAT-PERENTHALER SYNDROME
Identifiers:: MONDO: MONDO:0032895; MedGen: C5231487; OMIM: 618744

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001147001	OMIM	no assertion criteria provided	Pathogenic (Oct 21, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001827225	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 19, 2021)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002574742	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002820275	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003921984	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31820119, 25741868
SCV004040721	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004045777	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31820119, 25741868

Help

Summary from all submissions

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

Citations

PubMed

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Perenthaler E, Nikoncuk A, Yousefi S, Berdowski WM, Alsagob M, Capo I, van der Linde HC, van den Berg P, Jacobs EH, Putar D, Ghazvini M, Aronica E, van IJcken WFJ, de Valk WG, Medici-van den Herik E, van Slegtenhorst M, Brick L, Kozenko M, Kohler JN, Bernstein JA, Monaghan KG, Begtrup A, et al.

Acta Neuropathol. 2020 Mar;139(3):415-442. doi: 10.1007/s00401-019-02109-6. Epub 2019 Dec 9.

PubMed [citation]

PMID:: 31820119
PMCID:: PMC7035241

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV001147001.5

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

Description

In 20 patients from 13 unrelated families with infantile epileptic encephalopathy-83 (DEE83; 618744), Perenthaler et al. (2020) identified the same homozygous c.34A-G transition (NM_006759) at a highly conserved nucleotide in the UGP2 gene. The mutation was predicted to result in a met12-to-val (M12V) substitution in the longer isoform (isoform 1) and to disrupt a translational start site (c.1A-G, NM_001001521.1) in the shorter isoform (isoform 2), resulting in a met1-to-? (M1?) substitution. Isoform 2 of UGP2 is highly expressed in the brain and in neural stem cells. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. It was not present in several large control databases, including the Exome Variant Server and Iranone databases, but was found at a low frequency (5.3 x 10(-5)) in only heterozygous state in the gnomAD database (15 of 280,902 alleles). Western blot analysis of fibroblasts from 1 patient showed absent expression of the UGP2 short isoform, with upregulation of the long isoform harboring the M12V substitution. Whereas the 2 isoforms were equally expressed in wildtype fibroblasts, the expression of the shorter isoform was diminished to 25% of total UGP2 in heterozygous patients. These findings indicated that the long isoform carrying the M12V variant is upregulated when the short isoform is missing. The M12V long isoform showed normal cellular localization and enzymatic activity in patient cells, which may explain the survival of the patients. The families were of Middle Eastern descent, including Pakistani, Iranian, Saudi Arabian, Indian, and Omani, and haplotype analysis of several individuals suggested a founder effect. Although 1 family (family 1) was Dutch, the authors noted that Dutch traders settled in the region around Balochistan in the 17th century. The mutation was estimated to have originated about 26 generations or 600 years ago. Two additional patients from 2 additional unrelated families with a similar phenotype were also reported, although clinical details were not provided. Onset of the disorder in the patients ranged from the first days of life to about 7 months of age.

#	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 Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV001827225.2

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

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

From Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, SCV002574742.2

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV002820275.2

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

Description

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.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921984.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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

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

From Baylor Genetics, SCV004040721.1

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

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

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV004045777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (2)

Description

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".

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

Last Updated: Sep 29, 2024

Relating variation to medicine