Submissions for variant NM_007055.4(POLR3A):c.3392A>G (p.Lys1131Arg)

gnomAD frequency: 0.00006  dbSNP: rs138305578

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital	RCV000754394	SCV000786645	likely pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2018-05-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868192	SCV002138500	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 549572). This missense change has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30323018). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs138305578, gnomAD 0.03%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1131 of the POLR3A protein (p.Lys1131Arg).
Revvity Omics, Revvity	RCV001868192	SCV003811708	uncertain significance	not provided	2021-08-16	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003488783	SCV004232704	uncertain significance	Leukodystrophy	2024-01-24	criteria provided, single submitter	curation	The p.Lys1131Arg variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 30323018, Yananoto et al. 2017), and has been identified in 0.05% (13/24956) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138305578). 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. This Lys1131Arg variant has also been reported in ClinVar (Variation ID#: 549572) and has been interpreted as likely pathogenic by the Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital) and as a variant of uncertain significance by Invitae. Of the 2 affected individuals, 1 was a compound heterozygote that carried a likely pathogenic variant in trans, which increases the likelihood that the p.Lys1131Arg variant is pathogenic (PMID: 30323018). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Lys1131Arg variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30323018). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3, PM1_supporting (Richards 2015).