ClinVar Miner

Submissions for variant NM_198578.4(LRRK2):c.2264C>T (p.Pro755Leu)

gnomAD frequency: 0.00023  dbSNP: rs34410987
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000032422 SCV000378583 likely benign Autosomal dominant Parkinson disease 8 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000032422 SCV001021800 benign Autosomal dominant Parkinson disease 8 2023-10-11 criteria provided, single submitter clinical testing
GeneDx RCV001705621 SCV001882952 benign not provided 2021-05-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30598256, 25558820, 30049590, 17179858, 22575234, 24488318, 22988870, 20642453)
Fulgent Genetics, Fulgent Genetics RCV000032422 SCV002807085 likely benign Autosomal dominant Parkinson disease 8 2021-08-12 criteria provided, single submitter clinical testing
GeneReviews RCV000032422 SCV000056078 not provided Autosomal dominant Parkinson disease 8 no assertion provided literature only
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000032422 SCV001554168 likely benign Autosomal dominant Parkinson disease 8 no assertion criteria provided clinical testing The LRRK2 p.P755L variant was identified in several heterozygous individuals with Parkinson's disease; however, this variant was also identified in several unaffected controls (Yuan_2016_PMID: 27653456; Tomioyama_2008_PMID: 18923807; Di Fonzo_2006_PMID: 16633828; Tan_2008_PMID: 18265005). The variant was identified in dbSNP (ID: rs34410987) and ClinVar (classified as benign by Invitae and as likely benign by Illumina). The variant was identified in control databases in 198 of 282288 chromosomes at a frequency of 0.0007014, and was observed at the highest frequency in the East Asian population in 185 of 19908 chromosomes (freq: 0.009293) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.P755 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. Functional studies show that this variant has similar expression levels and activity compared to wild-type (Fava_2019_PMID: 31308240). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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