NM_004562.3:c.1310C>T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_004562.3(PRKN):c.1310C>T(p.Pro437Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00274 in 1,613,282 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004562.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00212 AC: 322AN: 152124Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00159 AC: 396AN: 249654Hom.: 0 AF XY: 0.00152 AC XY: 206AN XY: 135300
GnomAD4 exome AF: 0.00280 AC: 4093AN: 1461040Hom.: 8 Cov.: 31 AF XY: 0.00266 AC XY: 1930AN XY: 726804
GnomAD4 genome AF: 0.00212 AC: 322AN: 152242Hom.: 1 Cov.: 32 AF XY: 0.00183 AC XY: 136AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:1
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Reported previously in an individual with early onset Parkinson disease who also harbored a second PRKN variant; however, parental studies were not performed (PMID: 15108293); Reported previously as pathogenic in an individual with Parkinson disease who also harbored a complex locus rearrangement presumed to be on the other allele; however, parental testing was not performed and detailed clinical information was not available (PMID: 32802956); Reported previously in the heterozygous state in individuals with Parkinson disease; however, it was also observed in unaffected controls (PMID: 24660942, 17262853, 24167364, 30363439, 30099245, 37750340); Published functional studies demonstrate a damaging effect showing that P437L significantly reduced binding ability and ubiquitination activity of parkin (PMID: 16049031, 29893854); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33751372, 33045815, 33845304, 29893854, 30363439, 30099245, 17187375, 19636047, 12629236, 26683220, 29887346, 28189762, 18546294, 24167364, 17262853, 30994895, 20643691, 34426522, 34434164, 34584092, 15266615, 38378758, 38767677, 36909283, 32802956, 15108293, 16049031, 24660942, 37750340) -
not specified Uncertain:1
Variant summary: PRKN c.1310C>T (p.Pro437Leu) results in a non-conservative amino acid change located in the IBR domain (IPR002867) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 1613282 control chromosomes in the gnomAD database, including 9 homozygotes. c.1310C>T has been reported in the literature in individuals affected Parkinson disease/early onset PD (examples: Milanowski_2021, Castelo_2021, Lesage_2020, Pankratz_2009). These data do not allow any conclusion about variant significance. Functional studies have shown a damaging effect for P437L with reduced binding ability and ubiquitination activity of parkin (examples: Sriram_2005, Yi_2019) The following publications have been ascertained in the context of this evaluation (PMID: 30994895, 16049031, 33845304, 34434164, 33045815, 19636047). ClinVar contains an entry for this variant (Variation ID: 283504). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Lung cancer;C1140680:Ovarian cancer;C1868675:Autosomal recessive juvenile Parkinson disease 2 Uncertain:1
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Parkinson disease 12 Uncertain:1
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Autosomal recessive juvenile Parkinson disease 2 Benign:1
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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at