Submissions for variant NM_018082.6(POLR3B):c.2084-6A>G

gnomAD frequency: 0.00011  dbSNP: rs747912710

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484819	SCV000568202	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	RT-PCR studies of c.2084-6A>G indicate that it creates a cryptic splice acceptor site, leading to a frameshift and a premature stop codon at position 5 of the new reading frame (Daoud et al., 2013); This variant is associated with the following publications: (PMID: 27029625, 23355746, 25339210, 26478204, 31980526)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001195929	SCV001366353	pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2019-01-25	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM2,PM3,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000484819	SCV001446583	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000484819	SCV002011556	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV000484819	SCV002164863	pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in an abnormal splicing event and introduces a premature termination codon (PMID: 23355746). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 419962). This variant has been observed in individuals with leukodystrophy (PMID: 23355746, 25339210). This variant is present in population databases (rs747912710, gnomAD 0.02%). This sequence change falls in intron 19 of the POLR3B gene. It does not directly change the encoded amino acid sequence of the POLR3B protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001195929	SCV003761433	likely pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2023-05-02	criteria provided, single submitter	curation	The c.2084-6A>G variant in POLR3B has been reported in 9 compound heterozygous individuals with 4H leukodystrophy (PMID: 23355746, 25339210, 26478204, 27029625, 31577365), and has been identified in 0.02% (13/128322) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs747912710). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 9 affected individuals, 5 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the c.2084-6A>G variant is pathogenic (VariationID: 31166; PMID: 23355746, 25339210, 31577365). This variant has also been reported in ClinVar (Variation ID#: 419962) and has been interpreted as pathogenic by GeneDx, Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen), Centre for Mendelian Genomics (University Medical Centre Ljubljana), Institute for Clinical Genetics (University Hospital TU Dresden), and GeneReviews. In vitro functional studies provide some evidence that the c.2084-6A>G variant may impact protein function (PMID: 23355746). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. 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: PM3_strong, PS3_moderate, PP3 (Richards 2015)
Institute of Human Genetics, Heidelberg University	RCV001195929	SCV004814191	likely pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2024-03-01	criteria provided, single submitter	clinical testing
GeneReviews	RCV001195929	SCV001760703	not provided	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism		no assertion provided	literature only
OMIM	RCV001195929	SCV002102508	pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2022-03-04	no assertion criteria provided	literature only