Submissions for variant NM_033026.6(PCLO):c.8483C>T (p.Thr2828Ile)

gnomAD frequency: 0.00033  dbSNP: rs189352647

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001938395	SCV002197024	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2828 of the PCLO protein (p.Thr2828Ile). This variant is present in population databases (rs189352647, gnomAD 0.04%). 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: 1417472). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490941	SCV004241962	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: PCLO c.8483C>T (p.Thr2828Ile) results in a non-conservative amino acid change in 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 0.00021 in 248962 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.8483C>T in individuals affected with Pontocerebellar Hypoplasia Type 3 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics	RCV001938395	SCV005195644	uncertain significance	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV001938395	SCV005432967	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PCLO: BP4, BS1:Supporting