12-40310437-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_198578.4(LRRK2):c.4324G>C(p.Ala1442Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_198578.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Autosomal dominant Parkinson disease 8 Uncertain:1Other:1
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1442 of the LRRK2 protein (p.Ala1442Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Parkinson disease (PMID: 17427941, 22243833). ClinVar contains an entry for this variant (Variation ID: 39185). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRRK2 protein function. Experimental studies have shown that this missense change affects LRRK2 function (PMID: 20642453, 24375786, 25009464, 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at