ClinVar Miner

Submissions for variant NM_003690.5(PRKRA):c.665C>T (p.Pro222Leu)

gnomAD frequency: 0.00009  dbSNP: rs121434410
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000006718 SCV000992809 pathogenic Dystonia 16 2017-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000006718 SCV001136091 pathogenic Dystonia 16 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001786327 SCV002028673 pathogenic not provided 2023-12-03 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (PMID: 26231208); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22194846, 26231208, 34758253, 18243799, 25737287, 29279192, 25142429, 26990861, 31216405, 33049316, 31589614, 33606314)
Labcorp Genetics (formerly Invitae), Labcorp RCV000006718 SCV002148103 pathogenic Dystonia 16 2024-10-29 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 222 of the PRKRA protein (p.Pro222Leu). This variant is present in population databases (rs121434410, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive dystonia (PMID: 18243799, 25142429, 26990861). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6346). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRKRA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRKRA function (PMID: 26231208). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000006718 SCV002809852 pathogenic Dystonia 16 2021-10-26 criteria provided, single submitter clinical testing
3billion RCV000006718 SCV003841619 likely pathogenic Dystonia 16 2023-10-06 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.93 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 36287101). The variant has been reported to be associated with LAMB3 related disorder (PMID: 36287101). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000006718 SCV005916470 pathogenic Dystonia 16 2022-05-11 criteria provided, single submitter research
OMIM RCV000006718 SCV000026909 pathogenic Dystonia 16 2014-10-01 no assertion criteria provided literature only
Genomics England Pilot Project, Genomics England RCV000006718 SCV001760064 pathogenic Dystonia 16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003914817 SCV004730469 pathogenic PRKRA-related disorder 2024-02-23 no assertion criteria provided clinical testing The PRKRA c.665C>T variant is predicted to result in the amino acid substitution p.Pro222Leu. This variant was reported in the homozygous and compound heterozygous state in individuals with dystonia-parkinsonism and has been shown to segregate with disease in families (Camargos et al. 2008. PubMed ID: 18243799; Zech et al. 2014. PubMed ID: 25142429; Quadri et al. 2016. PubMed ID: 26990861; Dos Santos et al. 2017. PubMed ID: 29279192; Molloy et al. 2022. PubMed ID: 36186440). This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD . In vitro experimental studies suggest this variant impacts protein function (Vaughn et al. 2015. PubMed ID: 26231208; Burnett et al. 2020. PubMed ID: 33049316). This variant is interpreted as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.