Submissions for variant NM_006031.6(PCNT):c.4222C>T (p.Arg1408Trp)

gnomAD frequency: 0.00029  dbSNP: rs202161810

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001142468	SCV001302909	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2018-01-12	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001142468	SCV001477682	likely benign	Microcephalic osteodysplastic primordial dwarfism type II	2023-09-20	criteria provided, single submitter	clinical testing
Invitae	RCV002032352	SCV002315040	uncertain significance	not provided	2022-10-17	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 1408 of the PCNT protein (p.Arg1408Trp). This variant is present in population databases (rs202161810, gnomAD 0.05%). 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: 898542). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
GeneDx	RCV002032352	SCV002575274	uncertain significance	not provided	2022-09-20	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; This variant is associated with the following publications: (PMID: 26740555, 28719003)
Fulgent Genetics, Fulgent Genetics	RCV001142468	SCV002788581	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2022-05-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002559380	SCV003691528	uncertain significance	Inborn genetic diseases	2021-10-18	criteria provided, single submitter	clinical testing	The c.4222C>T (p.R1408W) alteration is located in exon 22 (coding exon 22) of the PCNT gene. This alteration results from a C to T substitution at nucleotide position 4222, causing the arginine (R) at amino acid position 1408 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003405347	SCV004111982	uncertain significance	PCNT-related condition	2024-01-08	criteria provided, single submitter	clinical testing	The PCNT c.4222C>T variant is predicted to result in the amino acid substitution p.Arg1408Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.051% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be an unreported disease-causing variant. 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.