Submissions for variant NM_033026.6(PCLO):c.5247A>C (p.Lys1749Asn)

dbSNP: rs370974945

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001938396	SCV002195453	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1749 of the PCLO protein (p.Lys1749Asn). This variant is present in population databases (rs370974945, 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: 1417473). 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	RCV003490942	SCV004241961	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: PCLO c.5247A>C (p.Lys1749Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 249042 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.5247A>C 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.
Ambry Genetics	RCV004043579	SCV005001424	uncertain significance	Inborn genetic diseases	2023-11-20	criteria provided, single submitter	clinical testing	The c.5247A>C (p.K1749N) alteration is located in exon 5 (coding exon 5) of the PCLO gene. This alteration results from a A to C substitution at nucleotide position 5247, causing the lysine (K) at amino acid position 1749 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV001938396	SCV005195722	uncertain significance	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV001938396	SCV005432968	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PCLO: BS1:Supporting