Submissions for variant NM_018082.6(POLR3B):c.1263+2T>C

gnomAD frequency: 0.00002  dbSNP: rs774526181

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578741	SCV000680665	pathogenic	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25339210, 32342562)
Fulgent Genetics, Fulgent Genetics	RCV000763294	SCV000893957	likely pathogenic	Hypogonadotropic hypogonadism 7 with or without anosmia; Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome; Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001542054	SCV003761380	likely pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2022-02-24	criteria provided, single submitter	curation	The c.1263+2T>C variant in POLR3B has been reported in at least 3 individuals with 4H leukodystrophy (PMID: 25339210) and has been identified in 0.002% (3/128790) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs774526181). 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. Of the 3 affected individuals, all were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the c.1263+2T>C variant is pathogenic (VariationID: 31166; PMID: 25339210). This variant has also been reported in ClinVar (Variation ID#: 488794) and has been interpreted as likely pathogenic or pathogenic by GeneDx, GeneReviews, and Fulgent Genetics. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated 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: PM2, PM3, PVS1_moderate (Richards 2015).
Invitae	RCV000578741	SCV004296197	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 13 of the POLR3B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLR3B are known to be pathogenic (PMID: 25339210). This variant is present in population databases (rs774526181, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with POLR3B-related conditions (PMID: 25339210). ClinVar contains an entry for this variant (Variation ID: 488794). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV001542054	SCV001760699	not provided	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism		no assertion provided	literature only