Submissions for variant NM_198578.4(LRRK2):c.5713G>C (p.Val1905Leu)

dbSNP: rs754436306

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000400697	SCV000378622	likely benign	Autosomal dominant Parkinson disease 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000400697	SCV000947858	uncertain significance	Autosomal dominant Parkinson disease 8	2018-11-12	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with LRRK2-related disease. ClinVar contains an entry for this variant (Variation ID: 308640). This variant is present in population databases (rs754436306, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces valine with leucine at codon 1905 of the LRRK2 protein (p.Val1905Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine.
Neuberg Centre For Genomic Medicine, NCGM	RCV000400697	SCV005382293	uncertain significance	Autosomal dominant Parkinson disease 8	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.5713G>C(p.Val1905Leu) variant in LRRK2 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Val1905Leu variant has been reported with allele frequency of 0.006% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Benign / Uncertain Significance. Multiple lines of computational evidences (Polyphen - Possibly damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 1905 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).