VCV000031166.67 - ClinVar

NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)

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.

(30)

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

This variant is part of a Genotype

NM_018082.5(POLR3B):c.[1568T>A];[1988C>T]

Identifiers

NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)

Variation ID: 31166 Accession: VCV000031166.67

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.3 12: 106432421 (GRCh38) [ NCBI UCSC ] 12: 106826199 (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	Apr 4, 2013	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_018082.6:c.1568T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060552.4:p.Val523Glu	missense
NM_001160708.2:c.1394T>A	NP_001154180.1:p.Val465Glu	missense
NC_000012.12:g.106432421T>A
NC_000012.11:g.106826199T>A
NG_031837.1:g.79764T>A
	Q9NW08:p.Val523Glu

... more HGVS ... less HGVS

Protein change

V523E, V465E

Other names

rs138249161
NM_018082.5(POLR3B):c.1568T>A
p.V523E

Canonical SPDI

NC_000012.12:106432420:T:A

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

probably has functional consequence

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.

0.00020 (A)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00027

Exome Aggregation Consortium (ExAC) 0.00028

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

The Genome Aggregation Database (gnomAD) 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00036

Links

ClinGen: CA343328 UniProtKB: Q9NW08#VAR_067006 OMIM: 614366.0005 dbSNP: rs138249161 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.
POLR3B		-	-	GRCh38 GRCh37	447	577

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.
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000032280.32
not provided	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000442312.47
Hypogonadotropic hypogonadism 7 with or without anosmia Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763295.10
POLR3-related leukodystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 6, 2020	RCV001095758.13
Hypogonadotropic hypogonadism	association (1)	no assertion criteria provided	Aug 10, 2016	RCV001849282.9
See cases	Pathogenic (1)	criteria provided, single submitter	Oct 6, 2020	RCV002251926.9
not specified	Pathogenic (1)	criteria provided, single submitter	Sep 22, 2022	RCV002285009.9
Charcot-Marie-Tooth disease, demyelinating, IIA 1I	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 9, 2023	RCV003334378.2
POLR3B-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 28, 2023	RCV004549388.2

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 (Jul 28, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000744101.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 7 with or without anosmia Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893958.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Feb 20, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	POLR3-related leukodystrophy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001360945.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (2) PubMed: 22036172‚ 23355746 Comment: Variant summary: POLR3B c.1568T>A (p.Val523Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: POLR3B c.1568T>A (p.Val523Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 276780 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in POLR3B causing POLR3-Related Leukodystrophy (0.0003 vs 0.0011), allowing no conclusion about variant significance. c.1568T>A has been reported in the literature in multiple individuals affected with POLR3-Related Leukodystrophy (Tetreault_2011, Daoud_2013) and is referred to as a common disease variant. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Oct 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523810.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: ACMG classification criteria: PS4, PM3, PP3 Clinical Features: Abnormality of mental function (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Heart murmur (present) , Myopia (present) , Polyneuropathy (present) , Neurodevelopmental … (more) Abnormality of mental function (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Heart murmur (present) , Myopia (present) , Polyneuropathy (present) , Neurodevelopmental abnormality (present) (less) Geographic origin: Brazil
Pathogenic (Mar 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761513.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Publications: PubMed (3) PubMed: 22036172‚ 23355746‚ 25339210 Comment: The POLR3B c.1568T>A variant is classified as Pathogenic (PS4, PM2, PM3_Strong, PP3) The POLR3B c.1568T>A variant is a single nucleotide change in exon 15/28 of … (more) The POLR3B c.1568T>A variant is classified as Pathogenic (PS4, PM2, PM3_Strong, PP3) The POLR3B c.1568T>A variant is a single nucleotide change in exon 15/28 of the POLR3B gene, which is predicted to change the amino acid valine at position 523 in the protein to glutamic acid. The variant has been reported in probands with a clinical presentation of Leukodystrophy. POLR3B:c.1568T>A has been described in the scientific literature in multiple patients with diffuse gastric cancer (Tétreault, et al, 2011, PMID: 22036172; Daoud et al., 2013 PMID: 23355746) (PS4). The variant is rare in population databases (PM2).This variant has been reported as compound heterozygous with another pathogenic variant, (POLR3B:c.2084-6A>G: clinvar ID 419962, POLR3B):c.2570+1G>A: clinvar ID 620581) in multiple unrelated individuals with POLR3B related leukodystrophy (Wolf et al., 2014, PMID:25339210) (PM3_Strong) (less)
Pathogenic (Feb 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003761423.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: The p.Val523Glu variant in POLR3B has been reported in >10 individuals with 4H leukodystrophy (PMID: 22036172, 25339210, 23355746), segregated with disease in 4 affected relatives … (more) The p.Val523Glu variant in POLR3B has been reported in >10 individuals with 4H leukodystrophy (PMID: 22036172, 25339210, 23355746), segregated with disease in 4 affected relatives from 4 families (PMID: 25339210), and has been identified in 0.06% (78/128850) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138249161). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 31166) and has been interpreted as pathogenic by multiple submitters. Of the many affected individuals, 1 of those were homozygote and 3 were compound heterozygotes that carried reported likely pathogenic variants in trans and with unknown phase, which increases the likelihood that the p.Val523Glu variant is pathogenic (VariationID: 1184082, 1184071, 31167; PMID: 22036172, 25339210, 23355746). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in POLR3B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PP3, PP1_strong, PM3_strong, PP2 (Richards 2015). (less)
Pathogenic (Feb 06, 2020)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Pol III-related leukodystrophy Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001251601.2 First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023	Publications: PubMed (3) PubMed: 26204956‚ 25339210‚ 23355746 Comment: The POLR3B c.1568T>A (p.Val523Glu) variant is a missense variant that has a well-documented association with Pol III-related leukodystrophy. Across a selection of the available literature, … (more) The POLR3B c.1568T>A (p.Val523Glu) variant is a missense variant that has a well-documented association with Pol III-related leukodystrophy. Across a selection of the available literature, the p.Val523Glu variant has been reported in a compound heterozyous state in over 50 affected individuals (Daoud et al. 2013; Wolf et al. 2014; Battini et al. 2015). In multiple cases, the variant was confirmed to be in trans with a known pathogenic variant. The p.Val1523Glu variant has been linked to a common ancestral haplotype with an estimated carrier frequency of 0.5% and tends to be associated with a milder phenotype. The p.Val1523Glu variant is reported at a frequency of 0.000605 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Val523Glu variant is classified as pathogenic for Pol III-related leukodystrophy. (less)
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001520343.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 11, 2023
Pathogenic (Aug 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, IIA 1I Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042808.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: ACMG criteria used to clasify this variant:PS4, PM3, PM2_SUP, PP1, PP2, PP3
Pathogenic (Apr 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	POLR3B-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004110849.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The POLR3B c.1568T>A variant is predicted to result in the amino acid substitution p.Val523Glu. This variant has been reported many times in the compound heterozygous … (more) The POLR3B c.1568T>A variant is predicted to result in the amino acid substitution p.Val523Glu. This variant has been reported many times in the compound heterozygous state in individuals with hypomyelinating leukodystrophy (Tétreault et al. 2011. PubMed ID: 22036172; Battini et al. 2015. PubMed ID: 26204956; Billington et al. 2015. PubMed ID: 26113998; Daoud et al. 2013. PubMed ID: 23355746; Ghoumid et al. 2017. PubMed ID: 28589944). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-106826199-T-A). Given the evidence, we interpret this variant as pathogenic. (less)
Pathogenic (May 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818512.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 19, 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: SCV002238537.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 22036172‚ 23355746‚ 25339210 Comment: This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 523 of the POLR3B protein … (more) This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 523 of the POLR3B protein (p.Val523Glu). This variant is present in population databases (rs138249161, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive hypomyelinating leukodystrophy (PMID: 22036172, 23355746, 25339210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLR3B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: maternal	Institute of Human Genetics, Heidelberg University Accession: SCV004814190.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Sex: female
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000514247.8 First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024	Comment: 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: 26113998, … (more) 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: 26113998, 26204956, 22036172, 26045207, 23355746, 27512013, 25131622, 29878067, 28589944, 24190003, 29552364, 29389947, 31221184, 32319736, 31589614, 32342562, 25339210, 35253369, 37974060, 35012964, 34737199, 35620261, 34758253) (less)
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440438.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020	Comment: This variant was identified as compound heterozygous.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001448126.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) , Leukoencephalopathy (present) , Cognitive impairment (present) Sex: female
Pathogenic (Sep 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Additional submitter: CUBI - Core Unit Bioinformatics, Berlin Institute of Health Accession: SCV002574815.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Clinical Features: Global developmental delay (present) , Microcephaly (present) , Cerebellar hypoplasia (present) , Developmental dysplasia of the hip (present) , Thyroglossal cyst (present) Sex: female Tissue: Blood
Likely pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011557.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099015.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PM2, PM3_Very Strong, PP2, PP3
Likely pathogenic (Dec 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, IIA 1I (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV005199887.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024	Publications: PubMed (5) PubMed: 23355746‚ 22036172‚ 25339210‚ 27512013‚ 32319736 Comment: This missense variant (c.1568T>A, p.Val523Glu) has been observed at extremely low frequency in population databases (gnomAD). It has been reported in the literature and variant … (more) This missense variant (c.1568T>A, p.Val523Glu) has been observed at extremely low frequency in population databases (gnomAD). It has been reported in the literature and variant prediction programs suggest a deleterious effect, although no functional studies have been published (PMID 22036172, PMID 23355746). This change has been found in five unrelated individuals, each carrying another heterozygous variant that is either pathogenic or of uncertain significance. No parental studies were performed. (less) Observation 1: Clinical Features: Cerebellar hypoplasia (present) , Cerebellar atrophy (present) , Cerebellar ataxia (present) , Myopia (present) , Delayed eruption of permanent teeth (present) Age: 0-9 years Sex: female Tissue: blood Observation 2: Clinical Features: Cerebellar hypoplasia (present) , Cerebellar atrophy (present) , Cerebellar ataxia (present) , Myopia (present) , Delayed eruption of permanent teeth (present) Age: 0-9 years Sex: female Tissue: blood Observation 3: Clinical Features: Cerebellar hypoplasia (present) , Motor delay (present) , Cerebellar vermis hypoplasia (present) , Abnormality of the dentition (present) Age: 0-9 years Sex: female Tissue: blood Observation 4: Clinical Features: Cerebellar hypoplasia (present) , Motor delay (present) , Cerebellar vermis hypoplasia (present) , Abnormality of the dentition (present) Age: 0-9 years Sex: female Tissue: blood Observation 5: Clinical Features: Delayed speech and language development (present) , Abnormality of bone mineral density (present) , Oligodontia (present) , Spasticity (present) , Hyperreflexia (present) Age: 0-9 years Sex: female Tissue: blood Observation 6: Clinical Features: Delayed speech and language development (present) , Abnormality of bone mineral density (present) , Oligodontia (present) , Spasticity (present) , Hyperreflexia (present) Age: 0-9 years Sex: female Tissue: blood Observation 7: Clinical Features: Cerebellar hypoplasia (present) , Pelvic kidney (present) , Motor delay (present) , Nystagmus (present) , Tremor (present) , Titubation (present) , Partial congenital absence of … (more) Cerebellar hypoplasia (present) , Pelvic kidney (present) , Motor delay (present) , Nystagmus (present) , Tremor (present) , Titubation (present) , Partial congenital absence of teeth (present) (less) Age: 0-9 years Sex: female Tissue: blood Observation 8: Clinical Features: Cerebellar hypoplasia (present) , Pelvic kidney (present) , Motor delay (present) , Nystagmus (present) , Tremor (present) , Titubation (present) , Partial congenital absence of … (more) Cerebellar hypoplasia (present) , Pelvic kidney (present) , Motor delay (present) , Nystagmus (present) , Tremor (present) , Titubation (present) , Partial congenital absence of teeth (present) (less) Age: 0-9 years Sex: female Tissue: blood Observation 9: Age: 0-9 years Sex: female Tissue: blood Observation 10: Age: 0-9 years Sex: female Tissue: blood
Pathogenic (Jul 01, 2024)	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: SCV001250406.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: POLR3B: PM3:Very Strong, PP1:Strong, PM2 Number of individuals with the variant: 5
Pathogenic (Dec 21, 2016)	no assertion criteria provided Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Biochimie-Hormonologie, Robert Debre Hospital Accession: SCV000564291.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017	Number of individuals with the variant: 1 Clinical Features: Oligodontia (present) , Cerebellar hypoplasia (present) , Short stature (present) , Ataxia (present) Age: 10-19 years Sex: male Ethnicity/Population group: Causasians Geographic origin: France
Pathogenic (Jan 30, 2015)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000746009.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760291.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952554.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001972652.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Nov 11, 2011)	no assertion criteria provided Method: literature only	LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH HYPODONTIA AND HYPOGONADOTROPIC HYPOGONADISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045453.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2022	Publications: PubMed (5) PubMed: 22036172‚ 25339210‚ 23355746‚ 28589944‚ 32319736 Comment on evidence: In 3 unrelated patients of European descent with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Tetreault et al. (2011) identified compound heterozygous mutations … (more) In 3 unrelated patients of European descent with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene. All had a heterozygous 1568T-A transversion in exon 15, resulting in a val523-to-glu (V523E) substitution. The other POLR3B mutations found in compound heterozygosity with V523E were a 1508C-A transversion in exon 15, resulting in a thr503-to-lys (T503K; 614366.0006) substitution; a 1-bp deletion (1533delT; 614366.0007) predicted to result in a frameshift and premature stop codon; and a 2686A-T transversion in exon 23, resulting in a lys896-to-ter (K896X; 614366.0008) substitution. Based on electron microscopy structure, the V523E and T503K substitutions were predicted be located near the 'jaw' of pol III, where other subunits are localized. Thus these mutations would affect local structure and impair proper function of pol III. None of the mutations were found in 340 control chromosomes, except for V523E, which was found in 2 (0.5%) of 374 control chromosomes. All patients presented in early childhood with mild developmental delays and developed dysarthria as well as progressive motor difficulties, including cerebellar ataxia. Two showed progressive spasticity. Two individuals developed hypogonadotropic hypogonadism, whereas the third was too young to evaluate for endocrine dysfunction. All 3 individuals had teeth abnormalities, such as neonatal upper incisors, delayed eruption of deciduous teeth and permanent teeth, abnormal sequence of eruption, and malposition. Brain MRI showed thin corpus callosum, cerebellar atrophy, and hypomyelination. Wolf et al. (2014) reported that 51 of 62 patients with HLD8 were compound heterozygous for the V523E variant and another mutation in the POLR3B gene. Only 1 sib pair was homozygous for V523E, and the sibs had an exceptionally mild clinical course, with the older sib having no neurologic signs at age 21 years. Brain MRI in the sibs showed much better myelination in the 2 homozygous sibs than in the other patients. In 2 unrelated patients (patients 8 and 9) with HLD8, Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2084-6A-G transition (IVS19-6A-G; 614366.0016) in intron 19, resulting in creation of a cryptic splice site and leading to a frameshift and premature termination (Gly695ValfsTer5). The mutations were identified by sequencing of the POLR3B gene. The V523E variant had an allele frequency of 0.5% in the dbSNP database. In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2274T-C transition resulting in a pro925-to-gln (P925Q; 614366.0015) substitution at a conserved site. The mutations were identified by Sanger sequencing of the POLR3B gene. The P925Q mutation was predicted to modify protein conformation. It was not present in the ExAC database. In a 21-year-old Dutch Caribbean woman with HLD8, Verberne et al. (2020) identified homozygosity for the V523E mutation. The mutation was found by sequencing of a gene panel of 761 genes associated with intellectual disability. Both parents were heterozygous for the mutation. The mutation was present in the gnomAD database at an allele frequency of 0.0003%. The patient had ataxia, developmental delay, and impaired intellectual development. (less)
Pathogenic (Apr 01, 2022)	no assertion criteria provided Method: clinical testing	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Accession: SCV003915645.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Number of individuals with the variant: 1 Clinical Features: Abnormality of the dentition (present) , Amblyopia (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dysmetria (present) , Slurred speech (present) , Joint … (more) Abnormality of the dentition (present) , Amblyopia (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dysmetria (present) , Slurred speech (present) , Joint laxity (present) , Dysdiadochokinesis (present) , Short stature (present) , Low-frequency sensorineural hearing impairment (present) , High myopia (present) , Midface retrusion (present) (less) Age: 0-9 years Sex: female Tissue: Blood
association (Aug 10, 2016)	no assertion criteria provided Method: literature only	Hypogonadotropic hypogonadism Affected status: yes Allele origin: de novo	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106491.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 27512013
not provided (-)	no classification provided Method: literature only	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000055916.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (5) PubMed: 22855961‚ 25339210‚ 22036172‚ 26045207‚ 24190003 BookShelf: NBK99167 BookShelf: NBK99167
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Comment:

Variant summary: POLR3B c.1568T>A (p.Val523Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 276780 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in POLR3B causing POLR3-Related Leukodystrophy (0.0003 vs 0.0011), allowing no conclusion about variant significance. c.1568T>A has been reported in the literature in multiple individuals affected with POLR3-Related Leukodystrophy (Tetreault_2011, Daoud_2013) and is referred to as a common disease variant. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The POLR3B c.1568T>A variant is classified as Pathogenic (PS4, PM2, PM3_Strong, PP3) The POLR3B c.1568T>A variant is a single nucleotide change in exon 15/28 of the POLR3B gene, which is predicted to change the amino acid valine at position 523 in the protein to glutamic acid. The variant has been reported in probands with a clinical presentation of Leukodystrophy. POLR3B:c.1568T>A has been described in the scientific literature in multiple patients with diffuse gastric cancer (Tétreault, et al, 2011, PMID: 22036172; Daoud et al., 2013 PMID: 23355746) (PS4). The variant is rare in population databases (PM2).This variant has been reported as compound heterozygous with another pathogenic variant, (POLR3B:c.2084-6A>G: clinvar ID 419962, POLR3B):c.2570+1G>A: clinvar ID 620581) in multiple unrelated individuals with POLR3B related leukodystrophy (Wolf et al., 2014, PMID:25339210) (PM3_Strong)

Comment:

The p.Val523Glu variant in POLR3B has been reported in >10 individuals with 4H leukodystrophy (PMID: 22036172, 25339210, 23355746), segregated with disease in 4 affected relatives from 4 families (PMID: 25339210), and has been identified in 0.06% (78/128850) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138249161). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 31166) and has been interpreted as pathogenic by multiple submitters. Of the many affected individuals, 1 of those were homozygote and 3 were compound heterozygotes that carried reported likely pathogenic variants in trans and with unknown phase, which increases the likelihood that the p.Val523Glu variant is pathogenic (VariationID: 1184082, 1184071, 31167; PMID: 22036172, 25339210, 23355746). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in POLR3B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PP3, PP1_strong, PM3_strong, PP2 (Richards 2015).

Comment:

The POLR3B c.1568T>A (p.Val523Glu) variant is a missense variant that has a well-documented association with Pol III-related leukodystrophy. Across a selection of the available literature, the p.Val523Glu variant has been reported in a compound heterozyous state in over 50 affected individuals (Daoud et al. 2013; Wolf et al. 2014; Battini et al. 2015). In multiple cases, the variant was confirmed to be in trans with a known pathogenic variant. The p.Val1523Glu variant has been linked to a common ancestral haplotype with an estimated carrier frequency of 0.5% and tends to be associated with a milder phenotype. The p.Val1523Glu variant is reported at a frequency of 0.000605 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Val523Glu variant is classified as pathogenic for Pol III-related leukodystrophy.

Comment:

The POLR3B c.1568T>A variant is predicted to result in the amino acid substitution p.Val523Glu. This variant has been reported many times in the compound heterozygous state in individuals with hypomyelinating leukodystrophy (Tétreault et al. 2011. PubMed ID: 22036172; Battini et al. 2015. PubMed ID: 26204956; Billington et al. 2015. PubMed ID: 26113998; Daoud et al. 2013. PubMed ID: 23355746; Ghoumid et al. 2017. PubMed ID: 28589944). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-106826199-T-A). Given the evidence, we interpret this variant as pathogenic.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 523 of the POLR3B protein (p.Val523Glu). This variant is present in population databases (rs138249161, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive hypomyelinating leukodystrophy (PMID: 22036172, 23355746, 25339210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLR3B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Comment:

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: 26113998, 26204956, 22036172, 26045207, 23355746, 27512013, 25131622, 29878067, 28589944, 24190003, 29552364, 29389947, 31221184, 32319736, 31589614, 32342562, 25339210, 35253369, 37974060, 35012964, 34737199, 35620261, 34758253)

Comment:

This missense variant (c.1568T>A, p.Val523Glu) has been observed at extremely low frequency in population databases (gnomAD). It has been reported in the literature and variant prediction programs suggest a deleterious effect, although no functional studies have been published (PMID 22036172, PMID 23355746). This change has been found in five unrelated individuals, each carrying another heterozygous variant that is either pathogenic or of uncertain significance. No parental studies were performed.

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
4H leukodystrophy caused by a homozygous POLR3B mutation: Further delineation of the phenotype.	Verberne EA	American journal of medical genetics. Part A	2020	PMID: 32319736
Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.	Ghoumid J	European journal of human genetics : EJHG	2017	PMID: 28589944
Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.	Richards MR	Journal of medical genetics	2017	PMID: 27512013
POLR3-Related Leukodystrophy.	Adam MP	-	2017	PMID: 22855961
Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.	Battini R	BMC medical genetics	2015	PMID: 26204956
Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.	Gutierrez M	Orphanet journal of rare diseases	2015	PMID: 26045207
Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.	Wolf NI	Neurology	2014	PMID: 25339210
Teaching neuroimages: hypomyelinating leukodystrophy with hypodontia due to POLR3B: look into a leukodystrophy's mouth.	Synofzik M	Neurology	2013	PMID: 24190003
Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.	Daoud H	Journal of medical genetics	2013	PMID: 23355746
Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy.	Tétreault M	American journal of human genetics	2011	PMID: 22036172

Text-mined citations for rs138249161 ...

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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138249161 ...