Submissions for variant NM_006031.6(PCNT):c.934C>T (p.Arg312Trp)

gnomAD frequency: 0.00015  dbSNP: rs572076735

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493816	SCV000582152	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PCNT gene. The R312W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R312W variant is observed in 7/36,328 (0.02%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R312W 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 in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000493816	SCV002156551	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the PCNT protein (p.Arg312Trp). This variant is present in population databases (rs572076735, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. 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: 429553). 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: "Probably 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.
Fulgent Genetics, Fulgent Genetics	RCV002475975	SCV002781370	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2021-07-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002524030	SCV003610993	uncertain significance	Inborn genetic diseases	2021-08-10	criteria provided, single submitter	clinical testing	The c.934C>T (p.R312W) alteration is located in exon 5 (coding exon 5) of the PCNT gene. This alteration results from a C to T substitution at nucleotide position 934, causing the arginine (R) at amino acid position 312 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000493816	SCV004026167	uncertain significance	not provided	2021-07-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419829	SCV004107891	uncertain significance	PCNT-related condition	2023-12-05	criteria provided, single submitter	clinical testing	The PCNT c.934C>T variant is predicted to result in the amino acid substitution p.Arg312Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Finnish) descent in gnomAD, including a homozygous individual. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.