NM_203290.4(POLR1C):c.326G>A (p.Arg109His) AND POLR1C-related disorder

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003387792.1

Allele description [Variation Report for NM_203290.4(POLR1C):c.326G>A (p.Arg109His)]

NM_203290.4(POLR1C):c.326G>A (p.Arg109His)

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.326G>A (p.Arg109His)

HGVS:

NC_000006.12:g.43519782G>A
NG_028283.3:g.15081G>A
NM_001318876.2:c.326G>A
NM_001363658.2:c.326G>A
NM_203290.4:c.326G>AMANE SELECT
NP_001305805.1:p.Arg109His
NP_001350587.1:p.Arg109His
NP_976035.1:p.Arg109His
NC_000006.11:g.43487520G>A
NM_203290.2:c.326G>A
NM_203290.3:c.326G>A
O15160:p.Arg109His

Protein change:

R109H; ARG109HIS

Links:

UniProtKB: O15160#VAR_074660; OMIM: 610060.0011; dbSNP: rs796052127

NCBI 1000 Genomes Browser:

rs796052127

Molecular consequence:

NM_001318876.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363658.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_203290.4:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: POLR1C-related disorder
Synonyms:: POLR1C-Related Disorders; POLR1C-related condition
Identifiers:: MONDO: MONDO:0700278; MedGen: CN239394

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004100231	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29644095, 33804237, 26151409, 31019026, 34645491, 33888711, 33597727 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004100231

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Sep 27, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization.

Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S, Nahas S, Cakici JA, Benson W, Kaplan RH, Kronick R, Bainbridge MN, Friedman J, Gold JJ, Ding Y, Veeraraghavan N, Dimmock D, Kingsmore SF.

NPJ Genom Med. 2018;3:10. doi: 10.1038/s41525-018-0049-4.

PubMed [citation]

PMID:: 29644095
PMCID:: PMC5884823

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.

Ching-López A, Martinez-Gonzalez LJ, Arrabal L, Sáiz J, Gavilán Á, Barbas C, Lorente JA, Roldán S, Sánchez MJ, Gutierrez-Ríos P.

Int J Mol Sci. 2021 Mar 15;22(6). doi:pii: 2990. 10.3390/ijms22062990.

PubMed [citation]

PMID:: 33804237
PMCID:: PMC8002209

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100231.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: POLR1C c.326G>A (p.Arg109His) results in a non-conservative amino acid change located in the DNA-directed RNA polymerase, insert domain (IPR011262) 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 8e-06 in 251486 control chromosomes (gnomAD). c.326G>A has been reported in the literature in compound heterozygous individuals affected with Leukodystrophy (Thiffault_2015, Farnaes_2018, Clark_2019, Yan_2021, De La Vega_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 33804237, 31019026, 34645491, 29644095, 33888711, 26151409, 33597727). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Oct 13, 2024

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