6-43520962-G-A

Position:

chr6-43520962-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_203290.4(POLR1C):c.836G>A(p.Arg279Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

POLR1C
NM_203290.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-43520961-C-T is described in Lovd as [Pathogenic].

PP5

Variant 6-43520962-G-A is Pathogenic according to our data. Variant chr6-43520962-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43520962-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLR1C	NM_203290.4 linkuse as main transcript	c.836G>A	p.Arg279Gln	missense_variant	8/9	ENST00000642195.1	NP_976035.1
POLR1C	NM_001318876.2 linkuse as main transcript	c.836G>A	p.Arg279Gln	missense_variant	8/11		NP_001305805.1
POLR1C	NM_001363658.2 linkuse as main transcript	c.836G>A	p.Arg279Gln	missense_variant	8/10		NP_001350587.1
POLR1C	XM_047419577.1 linkuse as main transcript	c.836G>A	p.Arg279Gln	missense_variant	8/9		XP_047275533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1C	ENST00000642195.1 linkuse as main transcript	c.836G>A	p.Arg279Gln	missense_variant	8/9		NM_203290.4	ENSP00000496044	P1	O15160-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251432

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000178

AC:

260

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000186

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000204

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 279 of the POLR1C protein (p.Arg279Gln). This variant is present in population databases (rs191582628, gnomAD 0.07%). This missense change has been observed in individuals with clinical features of Treacher Collins syndrome (PMID: 21131976, 30957429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30811). 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 expected to disrupt POLR1C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects POLR1C function (PMID: 26151409, 29567474). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2023	A different missense change at this residue (R279W) has been reported as pathogenic in the published literature and at GeneDx, in association with POLR1C-related disorder (PMID: 21131976); Published functional studies demonstrate that R279Q impairs targeting of the protein to the nucleolus and inhibits chondrogenic differentiation (PMID: 29567474, 26151409); 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: 26151409, 33558764, 35012964, 37197783, 30957429, 33804237, 31589614, 33726816, 36082953, 36271492, 21131976, 32042905, 29567474) -

Treacher Collins syndrome 3

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Treacher Collins syndrome 3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2-Supporting =>PM2 downgraded in strength to Supporting. PS3 => Well-established functional studies show a deleterious effect (PMID:29567474). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:21131976). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21131976). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PMID:21131976). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The POLR1C c.836G>A (p.Arg279Gln) missense variant has been reported in one study in which it was identified in a compound heterozygous state in three individuals, including two siblings, with Treacher Collins syndrome (Dauwerse et al. 2011). The p.Arg279Gln was also found in a heterozygous state in four unaffected family members. The variant was absent from 272 controls but is reported at a frequency of 0.00052 in the Latino population of the Exome Aggregation Consortium. Functional studies in HeLa cell lines stably expressing wild type or p.Arg279Gln-POLR1C demonstrated that the p.Arg279Gln variant did not affect polymerase assembly but did impair the targeting of the POLR1C protein to the nucleolus, the site of Pol I transcription (Thiffault et al. 2015). Based on the evidence, the p.Arg279Gln variant is classified as likely pathogenic for Treacher Collins syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2021

The c.836G>A (p.R279Q) alteration is located in exon 8 (coding exon 8) of the POLR1C gene. This alteration results from a G to A substitution at nucleotide position 836, causing the arginine (R) at amino acid position 279 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD) database, the POLR1C c.836G>A alteration was observed in 0.02% (54/282838) of total alleles studied, with a frequency of 0.07% (24/35440) in the Latino subpopulation. This mutation was identified in three individuals with Treacher Collins syndrome and a second POLR1C variant in trans (Dauwerse, 2011; Ghesh, 2019). It was also identified in two individuals with leukodystrophy; one individual was compound heterozygous and the other was homozygous for this mutation (Gauquelin, 2019). In COS7 and ATDC5 cells with this mutation, the protein localized to the lysosome rather than the nuclear regions (Matsumoto, 2018). The p.R279Q alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

POLR1C-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 12, 2022

Variant summary: POLR1C c.836G>A (p.Arg279Gln) results in a conservative amino acid change located in the DNA-directed RNA polymerase, RpoA/D/Rpb3-type domain (IPR011263) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251432 control chromosomes. This frequency does not allow conclusions about variant significance. c.836G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with POLR1C-Related Disorders, specifically Treacher-Collins syndrome and in cohorts with a diagnosis of childhood cerebellar ataxia, specifically hypomyelinating leukodystrophy (example, Dauwerse_2010, Ghesh_2019, Ching-Lopez_2021). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypomyelinating leukodystrophy 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

MyeliNeuroGene Lab, McGill University Health Center Research Institute

- -

Treacher Collins syndrome 3;C4225305:Hypomyelinating leukodystrophy 11

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

.;D;.;D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;.;.;D;D;.;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.57

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.9

.;M;.;M;.;M;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

.;D;D;.;.;D;.;.;.

REVEL

Pathogenic

0.73

Sift

Benign

0.030

.;D;D;.;.;D;.;.;.

Sift4G

Uncertain

0.042

.;D;D;.;.;D;.;.;.

Polyphen

1.0

.;D;.;D;.;D;.;D;.

Vest4

0.93, 0.87, 0.97

MVP

0.96

MPC

0.48

ClinPred

0.72

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.84

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over