VCV002159514.2 - ClinVar

NM_018082.6(POLR3B):c.2809C>T (p.Arg937Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018082.6(POLR3B):c.2809C>T (p.Arg937Ter)

Variation ID: 2159514 Accession: VCV002159514.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.3 12: 106496150 (GRCh38) [ NCBI UCSC ] 12: 106889928 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 20, 2024	Aug 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018082.6:c.2809C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060552.4:p.Arg937Ter	nonsense
NM_001160708.2:c.2635C>T	NP_001154180.1:p.Arg879Ter	nonsense
NC_000012.12:g.106496150C>T
NC_000012.11:g.106889928C>T
NG_031837.1:g.143493C>T

... more HGVS ... less HGVS

Protein change

R879*, R937*

Other names

NM_001160708.2:c.2635C>T

Canonical SPDI

NC_000012.12:106496149:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
POLR3B		-	-	GRCh38 GRCh37	447	577

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	Likely pathogenic (1)	criteria provided, single submitter	Feb 28, 2022	RCV003072854.2
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 4, 2023	RCV003085970.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003761443.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: The p.Arg937Ter variant in POLR3B has not been previously reported in the literature in individuals with 4H leukodystrophy but has been identified in 0.003% (1/30616) … (more) The p.Arg937Ter variant in POLR3B has not been previously reported in the literature in individuals with 4H leukodystrophy but has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs763154774). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 937, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). (less)
Pathogenic (Aug 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003472604.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 29141312‚ 25339210 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2159514). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2159514). This premature translational stop signal has been observed in individual(s) with POLR3B-related conditions (PMID: 29141312). This variant is present in population databases (rs763154774, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg937*) in the POLR3B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3B are known to be pathogenic (PMID: 25339210). (less)

Comment:

The p.Arg937Ter variant in POLR3B has not been previously reported in the literature in individuals with 4H leukodystrophy but has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs763154774). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 937, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2159514). This premature translational stop signal has been observed in individual(s) with POLR3B-related conditions (PMID: 29141312). This variant is present in population databases (rs763154774, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg937*) in the POLR3B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3B are known to be pathogenic (PMID: 25339210).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
[Clinical manifestation and gene analyses of 15 patients with intellectual disability or developmental delay complicated with congenital nystagmus].	Gao ZJ	Zhonghua er ke za zhi = Chinese journal of pediatrics	2017	PMID: 29141312
Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.	Wolf NI	Neurology	2014	PMID: 25339210

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_018082.6(POLR3B):c.2809C>T (p.Arg937Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...