ClinVar Miner

Submissions for variant NM_198578.4(LRRK2):c.3974G>A (p.Arg1325Gln)

gnomAD frequency: 0.00020  dbSNP: rs72546338
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000032449 SCV000826589 uncertain significance Autosomal dominant Parkinson disease 8 2024-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1325 of the LRRK2 protein (p.Arg1325Gln). This variant is present in population databases (rs72546338, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 18197194, 19405094, 21885347, 30598256). ClinVar contains an entry for this variant (Variation ID: 39175). 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 expected to disrupt LRRK2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRRK2 function (PMID: 35950872). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001731324 SCV001982910 uncertain significance not provided 2022-08-05 criteria provided, single submitter clinical testing Reported previously in individuals with Parkinson disease; however, the R1325Q variant was also observed in healthy control individuals in published literature (Zhang et al., 2018; Foo et al., 2014; Lesage et al., 2009); Reported as heterozygous in an individual with Parkinson disease and as homozygous in the individual's mother with tremor in published literature (Nuytemans et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19405094, 19472409, 31161537, 21885347, 18197194, 34426522, 20301387, 18973807, 30598256, 33272183, 33454605, 30049590, 24565865, 19357115, Kalogeropulou2022[functionalstudy])
Centogene AG - the Rare Disease Company RCV000032449 SCV002059832 likely pathogenic Autosomal dominant Parkinson disease 8 2021-04-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV000032449 SCV005049897 uncertain significance Autosomal dominant Parkinson disease 8 2024-01-25 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001731324 SCV005408306 uncertain significance not provided 2023-12-06 criteria provided, single submitter clinical testing BS2
GeneReviews RCV000032449 SCV000056106 not provided Autosomal dominant Parkinson disease 8 no assertion provided literature only

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