VCV000805980.20 - ClinVar

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

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.

(9)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 805980 Accession: VCV000805980.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p15 2: 63856320 (GRCh38) [ NCBI UCSC ] 2: 64083454 (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	Jan 27, 2020	Jul 23, 2024	Oct 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006759.4:c.34A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006750.3:p.Met12Val	missense
NM_001001521.1:c.1A>G
NM_001001521.2:c.1A>G	NP_001001521.1:p.Met1Val	missense initiator codon variant
NM_001377524.1:c.1A>G	NP_001364453.1:p.Met1Val	missense initiator codon variant
NM_001377525.1:c.1A>G	NP_001364454.1:p.Met1Val	missense initiator codon variant
NM_001377526.1:c.-496A>G		5 prime UTR
NM_001377527.1:c.-106+15088A>G		intron variant
NM_001377528.1:c.-415A>G		5 prime UTR
NM_001377529.1:c.-496A>G		5 prime UTR
NC_000002.12:g.63856320A>G
NC_000002.11:g.64083454A>G

... more HGVS ... less HGVS

Protein change

M1V, M12V

Other names

p.Met12Val

Canonical SPDI

NC_000002.12:63856319:A:G

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

Unknown function

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

Links

OMIM: 191760.0001 dbSNP: rs768305634 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.
UGP2		-	-	GRCh38 GRCh37	36	52

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, 83	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Oct 19, 2023	RCV000993844.15
D-6618	Likely pathogenic (1)	criteria provided, single submitter	-	RCV002273831.1
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 18, 2022	RCV001370354.5

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.
Likely pathogenic (May 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 83 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001827225.2 First in ClinVar: Sep 08, 2021 Last updated: Sep 03, 2023	Number of individuals with the variant: 1 Clinical Features: Recurrent urinary tract infections (present) , Inguinal hernia (present) , Vesicoureteral reflux (present) , Hydronephrosis (present) , Macroglossia (present) , Microcephaly (present) , Wide nasal … (more) Recurrent urinary tract infections (present) , Inguinal hernia (present) , Vesicoureteral reflux (present) , Hydronephrosis (present) , Macroglossia (present) , Microcephaly (present) , Wide nasal bridge (present) , Torticollis (present) , Conjunctivitis (present) , Hypermetropia (present) , Optic disc pallor (present) , Exotropia (present) , Horizontal nystagmus (present) , Reduced eye contact (present) , Hypertensive disorder (present) , Osteopenia (present) , Milia (present) , Tapered finger (present) , Intellectual disability (present) , Seizure (present) , Spasticity (present) , Global developmental delay (present) , Hypertonia (present) , Generalized hypotonia (present) , Dystonic disorder (present) , Hyperreflexia (present) , Ventricular septal defect (present) , Tachycardia (present) , Bradycardia (present) , Hyperconvex nail (present) , Anemia (present) , Dysphagia (present) , Constipation (present) , Gastroesophageal reflux (present) , Cerebral atrophy (present) , Hypoplasia of the corpus callosum (present) , Respiratory insufficiency (present) , Respiratory distress (present) , Asthma (present) , Ventriculomegaly (present) , Neurodegeneration (present) , Patchy alopecia (present) , Sleep abnormality (present) , Hypoplasia of the brainstem (present) , Developmental regression (present) , Abnormal autonomic nervous system physiology (present) , Hypsarrhythmia (present) , Intussusception (present) , Colitis (present) , Scoliosis (present) , Pathologic fracture (present) , Obstructive sleep apnea syndrome (present) , Generalized amyotrophy (present) , Chronic lung disease (present) , Developmental stagnation (present) , Focal-onset seizure (present) , Chronic oral candidiasis (present) , Peripheral neuropathy (present) , Short 5th metacarpal (present) , Vertical nystagmus (present) , Abnormal circulating glycine concentration (present) , Epileptic spasm (present) , Frontal hirsutism (present) , Nasogastric tube feeding in infancy (present) , Gastrostomy tube feeding in infancy (present) , Cardiac arrhythmia (present) , Punctate keratitis (present) , Bronchiolitis (present) , Abnormal circulating ornithine concentration (present) , Hypoxemia (present) , Infantile spasms (present) , Chronic pain (present) , Lagophthalmos (present) , Cerebral palsy (present) , Oliguria (present) , Cerebral visual impairment (present) , Epileptic encephalopathy (present) , Premature birth (present) , Abnormal delivery (present) , Neonatal hypoglycemia (present) , Neonatal respiratory distress (present) , Gestational diabetes (present) , Caesarian section (present) , Hyperemesis gravidarum (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Asian Indian Tissue: blood
Pathogenic (Aug 18, 2022)	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: SCV001566825.5 First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 31820119 Comment: This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the UGP2 protein (p.Met12Val). … (more) This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the UGP2 protein (p.Met12Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects UGP2 function (PMID: 31820119). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 805980). This missense change has been observed in individuals with clinical features of UGP2-related developmental and epileptic encephalopathy (PMID: 31820119; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs768305634, gnomAD 0.04%). (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	D-6618 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002558738.2 First in ClinVar: Aug 08, 2022 Last updated: Sep 03, 2023	Comment: Homozygous missense variation in exon 2 of UGP2 gene that result in the amino acid substitution of caline for methionine at codon 21 was detected. … (more) Homozygous missense variation in exon 2 of UGP2 gene that result in the amino acid substitution of caline for methionine at codon 21 was detected. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. (less) Clinical Features: Microcephaly (present) , Oligohydramnios (present) , Hyperbilirubinemia (present) , Seizure (present) Age: 0-9 years Sex: male Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (Jun 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy 83 Affected status: unknown Allele origin: germline	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV002574742.2 First in ClinVar: Sep 24, 2022 Last updated: Sep 03, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 83 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820275.2 First in ClinVar: Jan 21, 2023 Last updated: Sep 03, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Microcephaly (present) , Epileptic encephalopathy (present) , Global developmental delay (present)
Pathogenic (Mar 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 83 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004040721.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Oct 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 83 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital Accession: SCV004045777.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Publications: PubMed (1) PubMed: 31820119 Comment: 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 … (more) 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". (less)
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 83 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV003921984.3 First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 31820119 Comment: 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 … (more) 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 (less)
Pathogenic (Oct 21, 2020)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 83 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001147001.5 First in ClinVar: Jan 27, 2020 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 31820119 Comment on evidence: 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 … (more) 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. (less)

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the UGP2 protein (p.Met12Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects UGP2 function (PMID: 31820119). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 805980). This missense change has been observed in individuals with clinical features of UGP2-related developmental and epileptic encephalopathy (PMID: 31820119; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs768305634, gnomAD 0.04%).

Comment:

Homozygous missense variation in exon 2 of UGP2 gene that result in the amino acid substitution of caline for methionine at codon 21 was detected. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.

Comment:

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.

Comment:

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".

Comment:

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

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002558738.2

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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	Acta neuropathologica	2020	PMID: 31820119

Text-mined citations for rs768305634 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs768305634 ...