rs199504211

Variant names:

• chr12-106427339-T-C
• rs199504211
• NM_018082.6:c.1244T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2 PP5 BS1_Supporting

The NM_018082.6(POLR3B):​c.1244T>C​(p.Met415Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,613,792 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: POLR3B NM_018082.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:9 O:1
• Conservation: PhyloP100: 7.52
• Publications: 6 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 1 ACMG points.

• 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 12-106427339-T-C is Pathogenic according to our data. Variant chr12-106427339-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285205.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000643 (98/152328) while in subpopulation NFE AF = 0.00134 (91/68032). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3B	NM_018082.6	c.1244T>C	p.Met415Thr	missense_variant	Exon 13 of 28	ENST00000228347.9	NP_060552.4
POLR3B	NM_001160708.2	c.1070T>C	p.Met357Thr	missense_variant	Exon 13 of 28		NP_001154180.1
POLR3B	XM_017019621.3	c.1244T>C	p.Met415Thr	missense_variant	Exon 13 of 26		XP_016875110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3B	ENST00000228347.9	c.1244T>C	p.Met415Thr	missense_variant	Exon 13 of 28	1	NM_018082.6	ENSP00000228347.4
POLR3B	ENST00000539066.5	c.1070T>C	p.Met357Thr	missense_variant	Exon 13 of 28	2		ENSP00000445721.1
POLR3B	ENST00000549569.1	c.*9T>C		downstream_gene_variant		4		ENSP00000448398.1
POLR3B	ENST00000549195.1	n.*72T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000554 AC: 139 AN: 251068 AF XY: 0.000553

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000895 AC: 1308 AN: 1461464 Hom.: 1 Cov.: 32 AF XY: 0.000851 AC XY: 619 AN XY: 727058

African (AFR) AF: 0.000120 AC: 4 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00114 AC: 1266 AN: 1111704

Other (OTH) AF: 0.000497 AC: 30 AN: 60374

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74494

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.00158

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Pathogenic:4 Uncertain:1 Other:1

May 30, 2022

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 07, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Met415Thr variant in POLR3B has been reported in 7 individuals with 4H leukodystrophy (PMID: 27512013, 25133958, 27029625, 33726816, 34440436, 31996231), and has been identified in 0.11% (149/128840) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs199504211). 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#: 285205) and has been interpreted as VUS by multiple submitters, and likely pathogenic/pathogenic by multiple submitters. Of the 7 affected individuals, 2 were compound heterozygotes that carried reported pathogenic variants in trans, which increases the likelihood that the p.Met415Thr variant is pathogenic (VariationID: 620581; PMID: 31996231, 27512013). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PM3_strong, PP3_moderate, PP2 (Richards 2015). -

not provided Pathogenic:3 Uncertain:3

May 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2025

GeneDx

Significance: Pathogenic

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: 35316923, 27512013, 33726816, 34440436, 32870266, 27029625, 25133958, 32345981, 22855961, 37273706, 36268624) -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 415 of the POLR3B protein (p.Met415Thr). This variant is present in population databases (rs199504211, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive POLR3B-related conditions (PMID: 25133958, 27029625, 27512013, 34440436, 36268624, 37273706). ClinVar contains an entry for this variant (Variation ID: 285205). 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 not expected to disrupt POLR3B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3, PM3_strong -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLR3B: PM3:Very Strong, PM2:Supporting, PP2 -

Inborn genetic diseases Pathogenic:1

Aug 04, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1244T>C (p.M415T) alteration is located in exon 13 (coding exon 13) of the POLR3B gene. This alteration results from a T to C substitution at nucleotide position 1244, causing the methionine (M) at amino acid position 415 to be replaced by a threonine (T)._x000D_ _x000D_ Based on the available evidence, the c.1244T>C p.M415T alteration is classified as likely pathogenic for autosomal recessive POLR3B-related hypomyelinating leukodystrophy; however, it is unlikely to be causative of autosomal dominant POLR3B-related Charcot-Marie-Tooth disease type 1. Based on data from gnomAD, the C allele has an overall frequency of 0.06% (160/282446) total alleles studied. The highest observed frequency was 0.12% (149/128840) of European (non-Finnish) alleles. This variant has been reported to be compound heterozygous with other POLR3B variants in multiple individuals with features consistent with POLR3B-related hypomyelinating leukodystrophy (Fogel, 2014; La Piana, 2016; Richards, 2017; Barbosa-Gouveia, 2021; Gach, 2022). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

See cases Pathogenic:1

Nov 16, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4, PM3, PP3 -

Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism;C5676914:Charcot-Marie-Tooth disease, demyelinating, IIA 1I Pathogenic:1

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 20, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLR3B c.1244T>C (p.Met415Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00055 in 251068 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.1244T>C has been reported in the literature in individuals affected with POLR3-Related Leukodystrophy, cerebellar ataxia, isolated hypogonadotropic hypogonadism (Barbosa-Gouveia_2021, Fogel_2014, Richards_2017) and in an individual with clinical features of ataxia, myopia, developmental delay, short stature, and cerebellar atrophy (La Piana_2016). In all cases, the second allele reported in the patients were of unknown or uncertain significance. These reports do not provide unequivocal conclusions about association of the variant with POLR3-Related Leukodystrophy. 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: 34440436, 32345981, 32870266, 25133958, 27029625, 27512013, 33726816). ClinVar contains an entry for this variant (Variation ID: 285205). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Amenorrhea Uncertain:1

Mar 08, 2021

Yale Center for Mendelian Genomics, Yale University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

POLR-related leukodystrophy Uncertain:1

Sep 14, 2023

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLR3B c.1244T>C (p.Met415Thr) missense variant has been reported in at least five individuals with variable presentations of POLR3-related conditions, including ataxia, hypogonadotropic hypogonadism, white matter abnormalities on brain MRI, and myopia (PMID: 25133958; 27029625; 27512013; 33726816; 34440436). In two of these cases, the variant co-occurred with a predicted loss of function variant, and in at least three other cases it has been reported in trans with another missense variant. The highest frequency of this allele in the Genome Aggregation Database is 0.001337 in the European (non-Finnish) population (version 3.1.2). Computational evidence suggests the variant may impact the gene or gene product. Based on the available evidence, the c.1244T>C (p.Met415Thr) variant is classified as a variant of uncertain significance for POLR3-related leukodystrophy. -

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 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Uncertain:1

May 29, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.42	B;.
Vest4		0.98
MVP		0.78
MPC		1.1
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.71
gMVP		0.91
Mutation Taster		=9/91	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: rs199504211; hg19: chr12-106821117; COSMIC: COSV99075432; COSMIC: COSV99075432;