NM_203290.4(POLR1C):c.322C>T (p.His108Tyr) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 21, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV002253609.5

Allele description [Variation Report for NM_203290.4(POLR1C):c.322C>T (p.His108Tyr)]

NM_203290.4(POLR1C):c.322C>T (p.His108Tyr)

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.322C>T (p.His108Tyr)

HGVS:

NC_000006.12:g.43519778C>T
NG_028283.3:g.15077C>T
NM_001318876.2:c.322C>T
NM_001363658.2:c.322C>T
NM_203290.4:c.322C>TMANE SELECT
NP_001305805.1:p.His108Tyr
NP_001350587.1:p.His108Tyr
NP_976035.1:p.His108Tyr
NC_000006.11:g.43487516C>T
NM_203290.2:c.322C>T
NM_203290.3:c.322C>T

Protein change:

H108Y

Links:

dbSNP: rs1015942660

NCBI 1000 Genomes Browser:

rs1015942660

Molecular consequence:

NM_001318876.2:c.322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363658.2:c.322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_203290.4:c.322C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Mus musculus mutS homolog 4 (E. coli), mRNA (cDNA clone MGC:169787 IMAGE:8861182...
Mus musculus mutS homolog 4 (E. coli), mRNA (cDNA clone MGC:169787 IMAGE:8861182), complete cds
gi|187953830|gb|BC138163.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002525397	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 6, 2021)	germline	clinical testing	Citation Link,
SCV002936975	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32042905, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002525397

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 6, 2021)

germline

clinical testing

Citation Link,

SCV002936975

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2022)

germline

clinical testing

PubMed (2)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002525397.2

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

Description

Identified with a second POLR1C variant, phase unknown, in a patient with hypomyelination on brain MRI, microcephaly, and abnormal craniofacial development in the published literature (Gauquelin et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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: 33597727, 32042905, 33804237)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002936975.1

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

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 108 of the POLR1C protein (p.His108Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with leukodystrophy (PMID: 32042905). ClinVar contains an entry for this variant (Variation ID: 635142). 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 (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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

Last Updated: Sep 29, 2024

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