Submissions for variant NM_006031.6(PCNT):c.2833C>T (p.Arg945Cys)

gnomAD frequency: 0.00043  dbSNP: rs147358856

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193206	SCV000248461	uncertain significance	not specified	2014-12-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726051	SCV000341518	uncertain significance	not provided	2016-05-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000726051	SCV000525890	uncertain significance	not provided	2020-06-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; Has not been previously published as pathogenic or benign to our knowledge
Illumina Laboratory Services, Illumina	RCV001140497	SCV001300759	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726051	SCV002147151	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 945 of the PCNT protein (p.Arg945Cys). This variant is present in population databases (rs147358856, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. 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: 211849). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Ambry Genetics	RCV002517964	SCV003734915	uncertain significance	Inborn genetic diseases	2021-09-17	criteria provided, single submitter	clinical testing	The c.2833C>T (p.R945C) alteration is located in exon 15 (coding exon 15) of the PCNT gene. This alteration results from a C to T substitution at nucleotide position 2833, causing the arginine (R) at amino acid position 945 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
3billion, Medical Genetics	RCV001140497	SCV005328786	likely benign	Microcephalic osteodysplastic primordial dwarfism type II	2024-09-20	criteria provided, single submitter	clinical testing	The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.
PreventionGenetics, part of Exact Sciences	RCV003390929	SCV004112358	uncertain significance	PCNT-related disorder	2024-08-10	no assertion criteria provided	clinical testing	The PCNT c.2833C>T variant is predicted to result in the amino acid substitution p.Arg945Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.085% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be a primary cause of disease. Although we suspect this variant is benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.