Submissions for variant NM_006031.6(PCNT):c.7568C>T (p.Ala2523Val)

gnomAD frequency: 0.00004  dbSNP: rs368569999

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001141150	SCV001301476	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.
GeneDx	RCV001548524	SCV001768451	likely benign	not provided	2021-04-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Genetic Services Laboratory, University of Chicago	RCV001819846	SCV002070742	uncertain significance	not specified	2019-05-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001548524	SCV002143508	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2523 of the PCNT protein (p.Ala2523Val). This variant is present in population databases (rs368569999, gnomAD 0.1%), 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: 897705). 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 C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001141150	SCV005876043	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2024-11-21	criteria provided, single submitter	clinical testing	The PCNT c.7568C>T; p.Ala2523Val variant (rs368569999), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 897705). This variant is found predominantly in the South Asian population with an allele frequency of 0.1% (31/30404 alleles, including one homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.058). However, computational analyses (Alamut Visual Plus v.1.11) predict that this variant may impact splicing by creating a novel cryptic acceptor and a donor splice site. Due to conflicting information, the clinical significance of this variant is uncertain at this time.
PreventionGenetics, part of Exact Sciences	RCV003938495	SCV004762684	uncertain significance	PCNT-related disorder	2024-08-12	no assertion criteria provided	clinical testing	The PCNT c.7568C>T variant is predicted to result in the amino acid substitution p.Ala2523Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be a primary cause of disease. 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.