Submissions for variant NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)

gnomAD frequency: 0.00004  dbSNP: rs141659018

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cole/Wambach Lab, Washington University in St. Louis	RCV000755671	SCV000886476	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2018-10-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000994469	SCV001148006	likely pathogenic	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000994469	SCV002135625	pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 617894). This premature translational stop signal has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30414627, 30450527). 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 (rs141659018, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg254*) in the POLR3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002533777	SCV003761141	likely pathogenic	Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome	2023-01-24	criteria provided, single submitter	curation	The p.Arg254Ter variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with POLR3A-related disorders (PMID: 30450527, 30414627) and has been identified in 0.01% (3/24970) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs141659018). 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. This variant has also been reported in ClinVar (Variation ID#: 617894) and has been interpreted as pathogenic or likely pathogenic by multiple laboratories. This nonsense variant leads to a premature termination codon at position 254, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3 (Richards 2015).
GeneDx	RCV000994469	SCV003930553	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 30414627, 30450527)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330936	SCV004039082	pathogenic	POLR3-related leukodystrophy	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: POLR3A c.760C>T (p.Arg254X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251396 control chromosomes. c.760C>T has been reported in the literature at a compound heterozygous state with a second pathogenic variant in at-least one individual affected with Wiedemann-Rautenstrauch Syndrome (example, Wambach_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. These data indicate that the variant is very likely associated with POLR3A-associated diseases including Wiedemann-Rautenstrauch Syndrome and Pol III-Related Leukodystrophy. The following publication has been ascertained in the context of this evaluation (PMID: 30414627). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000755671	SCV000883073	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2024-04-02	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755671	SCV001479499	likely pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome		no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291256	SCV001479681	likely pathogenic	Wiedemann-Rautenstrauch-like progeroid syndrome		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000994469	SCV001959515	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000994469	SCV001972787	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV002507319	SCV002817114	not provided	Neonatal pseudo-hydrocephalic progeroid syndrome; Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome; Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism		no assertion provided	phenotyping only	Variant classified as Likely pathogenic and reported on 09-15-2021 by Lab or GTR ID 506526. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.