rs267608687

Variant names:

• chr12-106457147-G-A
• rs267608687
• NM_018082.6:c.2303G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP2 PP5

The NM_018082.6(POLR3B):​c.2303G>A​(p.Arg768His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,612,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R768C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3 O:1
• Conservation: PhyloP100: 9.96
• Publications: 9 publications found

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]

POLR3B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P
• hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease, demyelinating, IIA 1I

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• endosteal sclerosis-cerebellar hypoplasia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-106457146-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 973230.
• PP2: Missense variant in the POLR3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.1978 (above the threshold of 3.09). Trascript score misZ: 3.4842 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, neurodevelopmental disorder, endosteal sclerosis-cerebellar hypoplasia syndrome, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, Charcot-Marie-Tooth disease, demyelinating, IIA 1I.
• PP5: Variant 12-106457147-G-A is Pathogenic according to our data. Variant chr12-106457147-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31161.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.2303G>A	p.Arg768His	missense_variant	Exon 21 of 28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.2129G>A	p.Arg710His	missense_variant	Exon 21 of 28		NP_001154180.1
POLR3B	XM_017019621.3	c.2303G>A	p.Arg768His	missense_variant	Exon 21 of 26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.2303G>A	p.Arg768His	missense_variant	Exon 21 of 28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.2129G>A	p.Arg710His	missense_variant	Exon 21 of 28	2		ENSP00000445721.1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000836 AC: 21 AN: 251166 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1460612 Hom.: 0 Cov.: 30 AF XY: 0.0000674 AC XY: 49 AN XY: 726684

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.0000671 AC: 3 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1110964

Other (OTH) AF: 0.0000829 AC: 5 AN: 60342

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74366

African (AFR) AF: 0.0000723 AC: 3 AN: 41488

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000806 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 768 of the POLR3B protein (p.Arg768His). This variant is present in population databases (rs267608687, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of autosomal recessive hypomyelinating leukodystrophy (PMID: 22036171, 32180488; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31161). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLR3B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Nov 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 22855961, 26597493, 32180488, 22036171, 31589614) -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLR3B: PM2, PM5, PP3 -

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Pathogenic:2 Uncertain:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 28, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg768His variant in POLR3B has been reported in 3 individuals with 4H leukodystrophy (PMID: 22036171, 26597493, 32180488), and has been identified in 0.06% (18/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608687). 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. Of the 3 affected individuals, 1 of those was a homozygote and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Arg768His variant is pathogenic (VariationID: 31160; PMID: 22036171, 32180488). This variant has also been reported in ClinVar (Variation ID#: 31161) and has been interpreted as a VUS by GeneDx and pathogenic by GeneReviews and OMIM. 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, the clinical significance of the p.Arg768His variant is uncertain. ACMG/AMP Criteria applied: PP3, PP2, PM3_supporting (Richards 2015). -

Nov 11, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism (MIM#614381). Dominant negative is a suspected mechanism of disease for this gene and is associated with Charcot-Marie-Tooth disease, demyelinating, type 1I (MIM#619742) (PMID: 33417887). (I) 0108 - This gene is associated with both recessive and dominant disease. Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism has biallelic inheritance and Charcot-Marie-Tooth disease, demyelinating, type 1I has monoallelic inheritance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v4; 102 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 29 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0600 - Variant is located in the annotated RNA polymerase Rpb2, domain 6 (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change, p.(Arg768Cys), has been classified as likely pathogenic and VUS by clinical laboratories in ClinVar and has been reported in homozygous and compound heterozygous individuals with POLR3B-related features (PMIDs: 27029625, 32371413). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic/pathogenic multiple times and once as a VUS by clinical laboratories in ClinVar. It has also been identified in compound heterozygous and homozygous individuals with leukodystrophy (PMIDs: 22036171, 32180488). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

POLR-related leukodystrophy Pathogenic:1

Jun 23, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLR3B c.2303G>A (p.Arg768His) results in a non-conservative amino acid change located in the DNA-directed RNA polymerase, subunit 2, hybrid-binding domain (IPR007120) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251166 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. c.2303G>A has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with POLR3-Related Leukodystrophy (e.g. Saitsu_2011, Parayil Sankaran_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

POLR3B-related disorder Pathogenic:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLR3B c.2303G>A variant is predicted to result in the amino acid substitution p.Arg768His. This variant has been reported in the homozygous and compound heterozygous state in individuals with hypomyelinating leukodystrophy (Saitsu et al 2011. PubMed ID: 22036171; Parayil Sankaran et al. 2020. PubMed ID: 32180488). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

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

Jun 06, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PP5, PM5, PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Pathogenic	3.1	M;.
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.93
MVP		0.78
MPC		1.8
ClinPred		0.95	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.95
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267608687; hg19: chr12-106850925; COSMIC: COSV57285088;