NM_203290.4(POLR1C):c.193A>G (p.Met65Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV001861282.13

Allele description [Variation Report for NM_203290.4(POLR1C):c.193A>G (p.Met65Val)]

NM_203290.4(POLR1C):c.193A>G (p.Met65Val)

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.193A>G (p.Met65Val)

HGVS:

NC_000006.12:g.43519384A>G
NG_028283.3:g.14683A>G
NM_001318876.2:c.193A>G
NM_001363658.2:c.193A>G
NM_203290.4:c.193A>GMANE SELECT
NP_001305805.1:p.Met65Val
NP_001350587.1:p.Met65Val
NP_976035.1:p.Met65Val
NC_000006.11:g.43487122A>G
NM_203290.2:c.193A>G
NM_203290.3:c.193A>G
O15160:p.Met65Val

Protein change:

M65V

Links:

UniProtKB: O15160#VAR_074657; dbSNP: rs141471029

NCBI 1000 Genomes Browser:

rs141471029

Molecular consequence:

NM_001318876.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363658.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_203290.4:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002196685	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 22, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26151409, 32042905, 33804237, 28492532
SCV002586118	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Aug 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002196685

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 22, 2024)

germline

clinical testing

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

SCV002586118

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(Aug 1, 2022)

germline

clinical testing

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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants.

Gauquelin L, Cayami FK, Sztriha L, Yoon G, Tran LT, Guerrero K, Hocke F, van Spaendonk RML, Fung EL, D'Arrigo S, Vasco G, Thiffault I, Niyazov DM, Person R, Lewis KS, Wassmer E, Prescott T, Fallon P, McEntagart M, Rankin J, Webster R, Philippi H, et al.

Neurol Genet. 2019 Dec;5(6):e369. doi: 10.1212/NXG.0000000000000369.

PubMed [citation]

PMID:: 32042905
PMCID:: PMC6927361

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002196685.3

#	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 replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the POLR1C protein (p.Met65Val). This variant is present in population databases (rs141471029, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with POLR1C-related conditions (PMID: 26151409, 32042905, 33804237). ClinVar contains an entry for this variant (Variation ID: 356872). 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 not expected to disrupt POLR1C 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.

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV002586118.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	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		1	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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