Submissions for variant NM_007055.4(POLR3A):c.3013C>T (p.Arg1005Cys)

gnomAD frequency: 0.00002  dbSNP: rs267608682

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
DASA	RCV001824118	SCV002073761	likely pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2022-02-05	criteria provided, single submitter	clinical testing	The c.3013C>T;p.(Arg1005Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31149; PMID: 23965854; 22451160; 22036171; 21855841) - PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (RNA_pol_Rpb1_5) - PM1. The variant is present at low allele frequencies population databases (rs267608682 – gnomAD 0.0002386%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg1005Cys) was detected in trans with a pathogenic variant (PMID: 23965854; 22451160; 22036171; 21855841) - PM3. Pathogenic missense variant in this residue have been reported (ClinVar ID: 41246 - c.3014G>A;p.(Arg1005His)) - PM5. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Invitae	RCV001852565	SCV002109069	likely pathogenic	not provided	2023-01-22	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg1005 amino acid residue in POLR3A. Other variant(s) that disrupt this residue have been observed in individuals with POLR3A-related conditions (PMID: 22451160), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLR3A protein function. ClinVar contains an entry for this variant (Variation ID: 31149). This missense change has been observed in individual(s) with hypomyelinating leukodystrophy (PMID: 21855841, 22036171, 23355746). 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 (rs267608682, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1005 of the POLR3A protein (p.Arg1005Cys). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
MyeliNeuroGene Lab, McGill University Health Center Research Institute	RCV000024145	SCV002820977	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2022-09-01	criteria provided, single submitter	research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003488349	SCV004232664	likely pathogenic	Leukodystrophy	2024-01-24	criteria provided, single submitter	curation	The p.Arg1005Cys variant in POLR3A has been reported in 5 individual with hypomyelinating leukodystrophy (PMID:25339210, 34953043, 23355746, 21855841, 22036171), and has been identified in 0.009% (3/34590) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608682). 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#: 31149) and has been interpreted as pathogenic by GeneReviews and OMIM and likely pathogenic by Invitae and DASA. Of the 5 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg1005Cys variant is pathogenic (VariationID: 41245; PMID: 22036171). In vitro functional studies provide some evidence that the p.Arg1005Cys variant may impact protein function (PMID: 21855841). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Arg1005Cys 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: 21855841). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hypomyelinating leukodystrophy. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM1_supporting, PM2_supporting (Richards 2015).
OMIM	RCV000024145	SCV000045436	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2011-11-11	no assertion criteria provided	literature only
GeneReviews	RCV000024145	SCV000055889	not provided	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome		no assertion provided	literature only