rs138249161

Positions:

• chr12-106432421-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP2 PP3 PP5_Very_Strong

The NM_018082.6(POLR3B):​c.1568T>A​(p.Val523Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 O:2
• Conservation: PhyloP100: 7.64

Genes affected

POLR3B (HGNC:30348): (RNA polymerase III subunit B) This gene encodes the second largest subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The largest subunit and the encoded protein form the catalytic center of RNA polymerase III. Mutations in this gene are a cause of hypomyelinating leukodystrophy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR3B. . Gene score misZ 3.1978 (greater than the threshold 3.09). Trascript score misZ 3.4842 (greater than threshold 3.09). GenCC has associacion of gene with hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, endosteal sclerosis-cerebellar hypoplasia syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• PP5: Variant 12-106432421-T-A is Pathogenic according to our data. Variant chr12-106432421-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-106432421-T-A is described in Lovd as [Likely_pathogenic]. Variant chr12-106432421-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1568T>A	p.Val523Glu	missense_variant	15/28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.1394T>A	p.Val465Glu	missense_variant	15/28		NP_001154180.1
POLR3B	XM_017019621.3	c.1568T>A	p.Val523Glu	missense_variant	15/26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1568T>A	p.Val523Glu	missense_variant	15/28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.1394T>A	p.Val465Glu	missense_variant	15/28	2		ENSP00000445721.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251090 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135688

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000431 AC: 630 AN: 1461070 Hom.: 0 Cov.: 30 AF XY: 0.000392 AC XY: 285 AN XY: 726902

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000548

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000576 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Pathogenic:12 Other:1

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Feb 24, 2022	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). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochimie-Hormonologie, Robert Debre Hospital	Dec 21, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 30, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Apr 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 08, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 02, 2023	PM2, PM3_Very Strong, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Mar 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	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, 37787810) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	POLR3B: PM3:Very Strong, PP1:Strong, PM2 -

POLR3-related leukodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2024	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 0.00027 in 251090 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLR3B causing POLR3-Related Leukodystrophy, 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, Verberne_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22036172, 23355746, 35253369). ClinVar contains an entry for this variant (Variation ID: 31166). Based on the evidence outlined above, the variant was classified as pathogenic. -

Charcot-Marie-Tooth disease, demyelinating, IIA 1I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Aug 09, 2023	ACMG criteria used to clasify this variant:PS4, PM3, PM2_SUP, PP1, PP2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Dec 21, 2020	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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 22, 2022

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 06, 2020

ACMG classification criteria: PS4, PM3, PP3 -

Hypogonadotropic hypogonadism 7 with or without anosmia;C3280644:Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

POLR3B-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2023

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. -

Hypogonadotropic hypogonadism Other:1

association, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Aug 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.69	P;.
Vest4		0.96
MVP		0.80
MPC		1.3
ClinPred		0.82	D
GERP RS		6.1
Varity_R		0.86
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138249161; hg19: chr12-106826199;