Submissions for variant NM_007055.4(POLR3A):c.2617C>T (p.Arg873Ter)

gnomAD frequency: 0.00004  dbSNP: rs148932047

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224488	SCV000281068	pathogenic	not provided	2016-01-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000224488	SCV002019476	pathogenic	not provided	2023-09-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224488	SCV002229938	pathogenic	not provided	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg873*) 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). This variant is present in population databases (rs148932047, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neonatal progeriod syndrome and/or spastic ataxia (PMID: 27612211, 28459997). ClinVar contains an entry for this variant (Variation ID: 235466). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000224488	SCV002757567	pathogenic	not provided	2022-11-22	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; This variant is associated with the following publications: (PMID: 28459997, 27612211, 31589614)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002516224	SCV003761130	pathogenic	Leukodystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Arg873Ter variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 27612211, 28459997), and has been identified in 0.01% (2/19914) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs148932047). 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#: 235466) and has been interpreted as pathogenic by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), Invitae, OMIM, and PerkinElmer Genomics. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg873Ter variant is pathogenic (VariationID: 31144; PMID: 27612211). This nonsense variant leads to a premature termination codon at position 873, 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, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV004532823	SCV004109207	pathogenic	POLR3A-related disorder	2022-10-31	criteria provided, single submitter	clinical testing	The POLR3A c.2617C>T variant is predicted to result in premature protein termination (p.Arg873*). This variant has been reported in the compound heterozygous state in two individuals with autosomal recessive POLR3A related disorders (Jay et al. 2016. PubMed ID: 27612211; Minnerop et al. 2017. PubMed ID: 28459997). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-79753125-G-A). Nonsense variants in POLR3A are expected to be pathogenic. This variant is interpreted as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000224488	SCV004125824	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	POLR3A: PVS1, PM3:Strong, PM2
OMIM	RCV000755662	SCV000883061	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2019-02-13	no assertion criteria provided	literature only