Submissions for variant NM_018082.6(POLR3B):c.2774C>T (p.Pro925Leu)

gnomAD frequency: 0.00002  dbSNP: rs775141057

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001542029	SCV003761441	uncertain significance	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2022-02-28	criteria provided, single submitter	curation	The p.Pro925Leu variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 27029625), and has been identified in 0.004% (1/25122) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs775141057). 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#: 375248) and has been interpreted as pathogenic by GeneReviews and Biochimie-Hormonologie (Robert Debre Hospital). 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. In summary, the clinical significance of the p.Pro925Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PP2 (Richards 2015).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696909	SCV005197257	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing
Biochimie-Hormonologie, Robert Debre Hospital	RCV001542029	SCV000564290	pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2016-12-21	no assertion criteria provided	clinical testing
GeneReviews	RCV001542029	SCV001760669	not provided	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism		no assertion provided	literature only