Submissions for variant NM_007055.4(POLR3A):c.2350G>A (p.Gly784Ser)

gnomAD frequency: 0.00002  dbSNP: rs771786550

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001330345	SCV001521994	likely pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2019-12-06	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV001820022	SCV002064400	likely pathogenic	not provided	2017-06-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003490194	SCV004232675	likely pathogenic	Leukodystrophy	2024-01-24	criteria provided, single submitter	curation	The p.Gly784Ser variant in POLR3A has been reported in 3 individuals with hypomyelinating leukodystrophy (PMID: 23965854, 32342562, 25339210), and has been identified in 0.003% (1/29476) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs771786550). 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#: 1029125) and has been interpreted as likely pathogenic by Baylor Genetics and Genetic Services Laboratory (University of Chicago) and as pathogenic by GeneReviews. Of the 3 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Gly784Ser variant is pathogenic (PMID: 23965854). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hypomyelinating leukodystrophy.
Invitae	RCV001820022	SCV004295275	likely pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 784 of the POLR3A protein (p.Gly784Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of POLR3-related leukodystrophy (PMID: 23965854, 25339210, 27852030, 32342562). ClinVar contains an entry for this variant (Variation ID: 1029125). 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 expected to disrupt POLR3A protein function. 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.
GeneReviews	RCV001330345	SCV001760634	not provided	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome		no assertion provided	literature only