NM_203290.4(POLR1C):c.325C>T (p.Arg109Cys) AND Hypomyelinating leukodystrophy 11

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000788023.4

Allele description [Variation Report for NM_203290.4(POLR1C):c.325C>T (p.Arg109Cys)]

NM_203290.4(POLR1C):c.325C>T (p.Arg109Cys)

Gene:

POLR1C:RNA polymerase I and III subunit C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_203290.4(POLR1C):c.325C>T (p.Arg109Cys)

HGVS:

NC_000006.12:g.43519781C>T
NG_028283.3:g.15080C>T
NM_001318876.2:c.325C>T
NM_001363658.2:c.325C>T
NM_203290.4:c.325C>TMANE SELECT
NP_001305805.1:p.Arg109Cys
NP_001350587.1:p.Arg109Cys
NP_976035.1:p.Arg109Cys
NC_000006.11:g.43487519C>T
NM_203290.3:c.325C>T

Protein change:

R109C

Links:

dbSNP: rs1255115751

NCBI 1000 Genomes Browser:

rs1255115751

Molecular consequence:

NM_001318876.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363658.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_203290.4:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypomyelinating leukodystrophy 11
Identifiers:: MONDO: MONDO:0014666; MedGen: C4225305; Orphanet: 88637; OMIM: 616494

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000924595	MyeliNeuroGene Lab, McGill University Health Center Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	research	PubMed (2) [See all records that cite these PMIDs] 610060, 25741868
SCV004812293	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26151409, 33176815, 33888711, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000924595

MyeliNeuroGene Lab, McGill University Health Center Research Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

inherited

research

PubMed (2)
[See all records that cite these PMIDs]

SCV004812293

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 6, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	no	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Epididymal sarcoidosis: a report of two cases and a review of the literature.

Gerstenhaber BJ, Green R, Sachs FL.

Yale J Biol Med. 1977 Nov-Dec;50(6):669-75.

PubMed [citation]

PMID:: 610060
PMCID:: PMC2595577

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, et al.

Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623.

PubMed [citation]

PMID:: 26151409
PMCID:: PMC4506509

See all PubMed Citations (5)

Details of each submission

From MyeliNeuroGene Lab, McGill University Health Center Research Institute, SCV000924595.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV004812293.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change in POLR1C is predicted to replace arginine with cysteine at codon 109, p.(Arg109Cys). The arginine residue is highly conserved (98/98 vertebrates, UCSC), and is located in the RNA polymerase Rpb3/Rpb11 dimerisation domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.003% (1/34,592 alleles) in the Latino/admixed American population, which is consistent with a recessive disease. This variant has been detected in at least two individuals with a phenotype consistent with POLR3-related leukodystrophy. Both were compound heterozygous for the variant and a variant of uncertain significance on the second allele (PMID: 26151409, 33176815). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.908). Another missense variant c.326G>A, p.(Arg109His) in the same codon with a small difference in physicochemical properties has been classified as likely pathogenic for POLR3-related leukodystrophy (ClinVar ID: 204592; PMID: 26151409, 33888711). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3, PM5, PM2_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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