Submissions for variant NM_006031.6(PCNT):c.8398C>T (p.Arg2800Trp)

dbSNP: rs142608069

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147223	SCV000194590	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2014-04-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000520695	SCV000617051	uncertain significance	not provided	2015-04-14	criteria provided, single submitter	clinical testing	A variant of unknown significance has been identified in the PCNT gene. The R2800W variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R2800W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R2800W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved through mammals. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with epilepsy (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000520695	SCV002136312	uncertain significance	not provided	2021-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 2800 of the PCNT protein (p.Arg2800Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs142608069, ExAC 0.03%). 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: 159672). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
PreventionGenetics, part of Exact Sciences	RCV003415978	SCV004116645	uncertain significance	PCNT-related condition	2024-02-06	criteria provided, single submitter	clinical testing	The PCNT c.8398C>T variant is predicted to result in the amino acid substitution p.Arg2800Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.