Submissions for variant NM_007055.4(POLR3A):c.3014G>A (p.Arg1005His)

gnomAD frequency: 0.00002  dbSNP: rs200118797

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513333	SCV003441634	likely pathogenic	not provided	2024-05-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1005 of the POLR3A protein (p.Arg1005His). This variant is present in population databases (rs200118797, gnomAD 0.01%). This missense change has been observed in individuals with POLR3A-related leukodystrophy (PMID: 22451160, 25339210). ClinVar contains an entry for this variant (Variation ID: 41246). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg1005 amino acid residue in POLR3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21855841, 22036171, 23355746). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003488355	SCV004232663	uncertain significance	Leukodystrophy	2024-01-24	criteria provided, single submitter	curation	The p.Arg1005His variant in POLR3A has been reported in 4 individuals with hypomyelinating leukodystrophy (PMID: 22451160, 30389777, 2533921). This variant has been identified in 0.01% (3/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs200118797). 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#: 41246) and has been interpreted as pathogenic by GeneReviews. Of the 4 affected individuals, 1 was a compound heterozygote that carried reported a reported likely pathogenic variant in unknown phase and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Arg1005His variant is pathogenic (VariationID: 1184060, 41248; PMID: 2533921, 22451160). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant resulting in a different amino acid change at the same position, p.Arg1005Cys, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (VariationID: 31149; PMID: 21855841, 22036171). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3_supporting, PM5_supporting (Richards 2015).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795950	SCV005416943	likely pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome; Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5_Supporting+PP3+PP2+PM3
GeneReviews	RCV000034146	SCV000058081	not provided	Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome		no assertion provided	literature only