Submissions for variant NM_007055.4(POLR3A):c.3243-2A>G

gnomAD frequency: 0.00002  dbSNP: rs1462460124

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cole/Wambach Lab, Washington University in St. Louis	RCV000757953	SCV000886478	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2018-10-01	criteria provided, single submitter	research
Invitae	RCV001855900	SCV002135856	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 24 of the POLR3A 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 POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30414627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 619038). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002536571	SCV003761124	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2023-01-24	criteria provided, single submitter	curation	The c.3243-2A>G variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with POLR3A-related disorders (PMID: 30414627) and has been identified in 0.001% (1/112374) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1462460124). 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 variant has also been reported in ClinVar (Variation ID#: 619038) and has been interpreted as likely pathogenic or likely pathogenic by the Cole/Wambach Lab (Washington University in St. Louis), Invitae, and the University of Washington Center for Mendelian Genomics (University of Washington). This variant is located in the 5' splice region. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015).
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV002536571	SCV004045821	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2023-08-25	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000757953	SCV001479501	likely pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome		no assertion criteria provided	research