Submissions for variant NM_006031.6(PCNT):c.5994+4G>A

gnomAD frequency: 0.00008  dbSNP: rs781737632

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001697914	SCV000724520	likely benign	not provided	2018-11-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001140183	SCV001300409	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV001821743	SCV002065533	uncertain significance	not specified	2017-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV001697914	SCV002255072	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 28 of the PCNT gene. It does not directly change the encoded amino acid sequence of the PCNT protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs781737632, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PCNT-related conditions. ClinVar contains an entry for this variant (Variation ID: 513256). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.