Submissions for variant NM_018082.6(POLR3B):c.2302C>T (p.Arg768Cys)

gnomAD frequency: 0.00001  dbSNP: rs371453512

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249631	SCV001423595	likely pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2018-11-26	criteria provided, single submitter	clinical testing	[ACMG/AMP: PM2, PM5, PP2, PP3] This alteration is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249631	SCV003761437	uncertain significance	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2022-02-28	criteria provided, single submitter	curation	The p.Arg768Cys variant in POLR3B has been reported in 2 individuals with 4H leukodystrophy (PMID: 32371413, 27029625), and has been identified in 0.02% (2/10072) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs371453512). 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. Of the 2 affected individuals, 1 was a homozygote, which increases the likelihood that the p.Arg768Cys variant is pathogenic (PMID: 32371413). This variant has also been reported in ClinVar (Variation ID#: 973230) and has been interpreted as likely pathogenic/pathogenic by Institute for Genomic Medicine (IGM) Clinical Laboratory (Nationwide Children's Hospital) and GeneReviews. 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 number of missense variants reported in POLR3B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. One additional variant of uncertain significance, resulting in a different amino acid change at the same position, (p.Arg768His), has been reported in association with disease in the literature/ClinVar, though this information is not enough to determine pathogenicity (PMID: 26597493, 22036171, 32180488/Variation ID: 31161). In summary, the clinical significance of the p.Arg768Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PP2, PM3_supporting (Richards 2015).
GeneDx	RCV003319456	SCV004023875	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32371413, 27029625, 34490615)
Neuberg Centre For Genomic Medicine, NCGM	RCV003446665	SCV004171917	likely pathogenic	Charcot-Marie-Tooth disease, demyelinating, IIA 1I		criteria provided, single submitter	clinical testing
GeneReviews	RCV001249631	SCV001760666	not provided	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism		no assertion provided	literature only