Submissions for variant NM_033026.6(PCLO):c.7585A>G (p.Ile2529Val)

gnomAD frequency: 0.00021  dbSNP: rs574590559

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002002172	SCV002223960	uncertain significance	not provided	2024-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2529 of the PCLO protein (p.Ile2529Val). This variant is present in population databases (rs574590559, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with PCLO-related conditions. ClinVar contains an entry for this variant (Variation ID: 1448156). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics	RCV003264330	SCV003949528	likely benign	Inborn genetic diseases	2023-05-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Neuberg Centre For Genomic Medicine, NCGM	RCV004720347	SCV005329440	uncertain significance	Pontocerebellar hypoplasia type 3	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.7585A>G(p.Ile2529Val) in PCLO gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.02% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Isoleucine at position 2529 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782832	SCV005395182	uncertain significance	not specified	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: PCLO c.7585A>G (p.Ile2529Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 248524 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PCLO causing Pontocerebellar Hypoplasia Type 3, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7585A>G in individuals affected with Pontocerebellar Hypoplasia Type 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1448156). Based on the evidence outlined above, the variant was classified as uncertain significance.