Submissions for variant NM_007055.4(POLR3A):c.1909+22G>A

gnomAD frequency: 0.00156  dbSNP: rs191875469

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514925	SCV000610762	pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital	RCV000754390	SCV000786641	likely pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2018-05-01	criteria provided, single submitter	research
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000754390	SCV000930453	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2023-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000514925	SCV001134970	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Identified in multiple unrelated patients with POLR3A-related disorders tested at GeneDx and in the published literature who had different pathogenic variants on the opposite allele (La Piana et al., 2016; Minnerop et al., 2017; Travaglini et al., 2018) Functional studies suggest this variant generates a "leaky" cryptic donor site that results in the inclusion of part of intron 14 (Minnerop et al., 2017) In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect Observed in 0.1365% (386/282828 alleles) in large population cohorts (Lek et al., 2016).
Mendelics	RCV000988394	SCV001138096	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514925	SCV001247298	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLR3A: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting
Illumina Laboratory Services, Illumina	RCV001249723	SCV001423749	pathogenic	POLR3A-related neurological disorders	2020-03-02	criteria provided, single submitter	clinical testing	The POLR3A c.1909+22G>A variant is an intronic variant. Across a selection of the available literature, the c.1909+22G>A variant has been identified in at least 30 unrelated individuals in a compound heterozygous state, all presenting with limb and gait ataxia. Tremor in the upper and lower limbs, dental problems, myopia, dysarthria, and dysphagia were also noted in some of these individuals. In addition, brain MRIs showed hyperintensities along the cerebellar peduncles, cervical cord atrophy, and hypoplasia of the corpus callosum (Minnerop et al. 2017; Rydning et al. 2019; Infante et al. 2020). Mild hypomyelination was also observed in some affected individuals (Rydning et al. 2019). The c.1909+22G>A variant was also present one individual in a homozygous state, primarily presenting with childhood-onset axonal neuropathy, in addition to gait ataxia (Minnerop et al. 2017). At least seven families had multiple affected individuals with the variant in a compound heterozygous state (Minnerop et al. 2017; Rydning et al. 2019; Infante et al. 2020). Evaluation of PCR products from affected individuals and healthy controls indicated that the variant affects splicing of exon 14, although this effect may be incomplete. In addition, inhibition of nonsense medicated mRNA decay in fibroblasts from affected individuals suggested the aberrantly spliced transcript due to the c.1909+22G>A variant is subject to nonsense mediated decay. In addition, gene and protein expression were reduced in the presence of the variant compared to controls (Minnerop et al. 2017). The c.1909+22G>A variant is reported at a frequency of 0.002238 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the c.1909+22G>A variant is classified as pathogenic for POLR3A-related neurological disorders.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000514925	SCV001446415	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000754390	SCV001519178	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome	2021-01-04	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514925	SCV001583974	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. This variant is present in population databases (rs191875469, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with clinical features of POLR3A-related leukodystrophies (PMID: 27029625, 28459997, 29691679, 30323018, 30847471, 31637490). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 445922). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28459997, 30323018). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000514925	SCV002019479	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000988394	SCV002557627	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (MIM#607694), Wiedemann-Rautenstrauch syndrome (MIM#264090) and POLR3A-related spastic ataxia (PMID: 31637490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Functional analysis of patient leucocyte-derived cDNA, has demonstrated that this variant results in the leaky inclusion of 19 nucleotides in intron 14. This results in a shift in the reading frame, and the production of a protein with a premature termination codon (p.Tyr637Cysfs*14), shown to be degraded by nonsense mediated decay (PMID: 28459997). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (386 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant as been reported many times as pathogenic, and has been observed in at least 30 compound heterozygous individuals with limb and gait ataxia (ClinVar). It has also been observed in a homozygous individual with childhood-onset axonal neuropathy (PMID: 28459997), and segregated in another family with spastic ataxia and hypodontia, who had an additional pathogenic splice variant in cis (PMID: 33491183). (SP) 1207 - Parental origin of the variant is unresolved (by quad analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Variantyx, Inc.	RCV002448556	SCV002754528	pathogenic	POLR3A-related disorder	2022-11-07	criteria provided, single submitter	clinical testing	This is a non-canonical splice variant in the POLR3A gene (OMIM 614258). Biallelic pathogenic variants in this gene have been associated with autosomal recessive POLR3A-related disorders. Functional studies demonstrate that this variant disrupts mRNA splicing leading to premature termination and nonsense-mediated mRNA decay (PMID: 28459997, 30323018) (PVS1). This variant has been reported in the homozygous or compound heterozygous state in many unrelated affected individuals (PMID: 28459997, 29691679, 30847471, 31637490) (PM3_Very Strong). This variant has been observed to segregate with disease in multiple affected families (PMID: 30847471, 31637490) (PP1_Strong). This variant has a 0.2763 % maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive POLR3A-related disorders.
Ambry Genetics	RCV002528232	SCV003718066	pathogenic	Inborn genetic diseases	2021-10-07	criteria provided, single submitter	clinical testing	The c.1909+22G>A intronic alteration results from a G to A substitution 22 nucleotides after coding exon 14 of the POLR3A gene. The c.1909+22G>A alteration is a hypomorphic allele that has been reported in the homozygous state and in trans with a second loss of function alteration in multiple unrelated patients with an autosomal recessive spastic ataxic phenotype with mild dental involvement and hyperintensities along the superior cerebellar peduncles (Minnerop, 2017; Rydning, 2019; Morales-Rosado, 2020; de Assis Pereira Matos, 2020). This alteration has been shown to cosegregate with disease in one family with four affected siblings (Minnerop, 2017). In a case-control study, the c.1909+22G>A variant was significantly associated (P = 1.3 x 10-4, odds ratio = 3.11) with hereditary spastic paraplegia, cerebellar ataxia, and/or neuropathy cases compared to other disease phenotypes and healthy controls (Minnerop, 2017). In addition, the c.1909+22G>A alteration has been reported in cis with c.3337-11T>C in several patients with Wiedemann-Rautenstrauch syndrome who carried this complex allele in trans with a second loss of function alteration (Paolacci, 2018). This nucleotide position is not well conserved in available vertebrate species. Functional RNA studies of c.1909+22G>A demonstrated a mild effect on splicing due to activation of an out of frame cryptic splice site which resulted in partial intron 14 retention and a transcript that was partially degraded by nonsense mediated decay (Minnerop, 2017; Rydning, 2019; Morales-Rosado, 2020). RNA studies in two patients who harbored the complex allele [c.1909+22G>A; c.3337-11T>C] demonstrated that both variants resulted in aberrant splicing and thus the additive effect on splicing was proposed to be a greater loss of function allele associated with a more severe phenotype (Paolacci, 2018). In addition, another variant affecting the same splice site (c.1909+18G>A) also demonstrated aberrant splicing on functional studies (Bernard, 2011). In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000754390	SCV003841199	pathogenic	Neonatal pseudo-hydrocephalic progeroid syndrome		criteria provided, single submitter	clinical testing
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV002448556	SCV003920806	pathogenic	POLR3A-related disorder	2023-04-27	criteria provided, single submitter	research
3billion	RCV000988394	SCV004013835	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome		criteria provided, single submitter	clinical testing	The intronic variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.136%). Although in silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.10), a study showed that alternative splicing having the first 19 nucleotides of intron 14 included in the transcript resulted in a shift of the reading frame (PMID: 28459997). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28459997, 30323018, 30847471). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the the same family or similarly affected unrelated family (PMID: 28459997). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000445922/PMID: 27029625). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000988394	SCV004045822	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2023-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403205	SCV004122078	pathogenic	POLR3-related leukodystrophy	2023-10-24	criteria provided, single submitter	clinical testing	Variant summary: POLR3A c.1909+22G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens a canonical 5' donor site. Three predict the variant strengthens a cryptic 5' donor site. Functional studies suggest this variant activates a "leaky" cryptic donor site that results in the inclusion of part of intron 14, and the production of a protein with a premature termination codon (p.Tyr637Cysfs*14), shown to be degraded by nonsense mediated decay (Minnerop_2017, Paolacci_ 2018). c.1909+22G>A has been reported in the literature in homozygous state and in trans with a loss of function alteration in multiple unrelated patients affected with autosomal recessive spastic ataxic phenotype (Minnerop_ 2017). Additionally, it has also been reported in individuals affected with leukodystrophy (Macken_ 2022) and Wiedemann-Rautenstrauch syndrome (Paolacci_ 2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28459997, 30323018, 36344503). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=15) as well as uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000988394	SCV004232684	pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2024-01-24	criteria provided, single submitter	curation	The c.1909+22G>A variant in POLR3A has been reported in >10 individuals with POLR3A-related disorders (PMID: 28459997, 30323018), segregated with disease in 4 affected relatives from 2 families (PMID: 28459997), and has been identified in 0.2% (289/129138) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs191875469). 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#: 445922) and has been interpreted as likely pathogenic or pathogenic by multiple laboratories, as well as a variant of uncertain significance by a few additional labs. Of the 18 affected individuals, 1 of those was a homozygote and 8 were compound heterozygotes that carried reported pathogenic and likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the c.1909+22G>A variant is pathogenic (VariationID: 684773; PMID: 28459997). In vitro functional studies provide some evidence that the c.1909+22G>A variant may impact protein function (PMID: 28459997). However, these types of assays may not accurately represent biological function. This variant is located in the 3’ splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. This variant was also detected in 1 homozygous and supposedly unaffected Palestinian individual (PMID:30323018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PS3_moderate, PM3_strong, PP1_strong (Richards 2015).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000988394	SCV004807190	likely pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2024-03-26	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993993	SCV004812517	pathogenic	Spastic ataxia	2022-04-01	criteria provided, single submitter	clinical testing	This sequence change in POLR3A is an intronic variant located in intron 14. The highest population minor allele frequency in gnomAD v2.1 is 0.2% (289/129,138 alleles) in the European (non-Finnish) population. This variant has been detected homozygous or compound heterozygous with a second allele in at least 19 individuals with spastic ataxia with/without dental abnormalities, segregating with disease in at least two of these families (PMID: 28459997). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) are conflicting on whether this variant may impact splicing by creation of a de novo donor splice site of intron 14 of POLR3A. This prediction is confirmed by RT-PCR. The assay demonstrated that the variant impacts splicing by activation of a leaky cryptic donor site leading to 19 bp intron 14 inclusion (p.Tyr637Cysfs*14). The variant has been described as a hypomorph, because it leads to leaky cryptic donor activation and is not associated with the classic POLR3A-related leukodystrophy phenotype (PMID: 28459997). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000988394	SCV005199891	likely pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2019-01-09	criteria provided, single submitter	clinical testing	This intronic variant (c.1909+22G>A) was observed at extremely low frequency in population databases (gnomAD). The variant adds 19 bases of intron 14 to the transcript and creates an alternate splice site, resulting in premature truncation. The change has been reported in the literature, and published studies indicate a decrease in POLR3A protein (PMID 28459997, PMID 30323018, PMID 21855841). This heterozygous change was seen in an affected individual, although no other pathogenic or likely pathogenic variants were found within the regions of the POLR3A examined.
Baylor Genetics	RCV000988394	SCV001521993	uncertain significance	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2019-09-25	flagged submission	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genomics England Pilot Project, Genomics England	RCV000988394	SCV001760259	likely pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome		no assertion criteria provided	clinical testing
GeneReviews	RCV000988394	SCV001760626	not provided	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome		no assertion provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000514925	SCV001927538	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514925	SCV001972286	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001814996	SCV002061954	uncertain significance	not specified	2018-05-30	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV002506245	SCV002817113	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 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.
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000988394	SCV003927902	likely pathogenic	Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	2023-04-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV002448556	SCV004116147	likely pathogenic	POLR3A-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The POLR3A c.1909+22G>A variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous states in multiple families with variable-onset ataxia with or without tremor (La Piana et al. 2016. PubMed ID: 27029625; Minnerop et al. 2017. PubMed ID: 28459997; Travaglini et al. 2018. PubMed ID: 29691679; D'Amore et al. 2018. PubMed ID: 30564185; Paolacci et al. 2018. PubMed ID: 30323018; Rydning et al. 2019. PubMed ID: 30847471; Infante et al. 2020. PubMed ID: 31637490; de Assis Pereira Matos et al. 2020. PubMed ID: 32373668; Ruggiero et al. 2020. PubMed ID: 33085208). Additional studies indicate that the c.1909+22G>A variant, which is postulated to be a hypomorphic variant, generates a novel cryptic splice donor site, leading to a frameshift and premature protein termination; the resulting transcript is subject to nonsense-mediated mRNA decay (Minnerop et al. 2017. PubMed ID: 28459997). The c.1909+22G>A variant is reported at a minor allele frequency of up to ~0.22% in one large continental population but is not reported in the homozygous state. Based on the available evidence, we classify the c.1909+22G>A variant as likely pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV004698500	SCV005200157	likely pathogenic	Movement disorder		no assertion criteria provided	clinical testing	Intron retention confirmed in other study (PMID 32597037)