Submissions for variant NM_006031.6(PCNT):c.5582C>T (p.Ala1861Val)

gnomAD frequency: 0.00011  dbSNP: rs373238616

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000357970	SCV000437019	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	RCV000357970	SCV001473360	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2020-03-13	criteria provided, single submitter	clinical testing	The PCNT c.5582C>T; p.Ala1861Val variant (rs373238616), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 340503). This variant is found in the Latino population with an overall allele frequency of 0.03% (9/34500 alleles) in the Genome Aggregation Database. The alanine at codon 1861 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Ala1861Val variant is uncertain at this time.
GeneDx	RCV001770274	SCV001992103	uncertain significance	not provided	2020-07-30	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a clinically unaffected adult individual in published literature (Chen et al., 2016); 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: 27323140)
Invitae	RCV001770274	SCV002147846	uncertain significance	not provided	2022-05-20	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 1861 of the PCNT protein (p.Ala1861Val). This variant is present in population databases (rs373238616, gnomAD 0.02%). 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: 340503). 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"). 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	RCV003910332	SCV004718422	uncertain significance	PCNT-related condition	2024-02-28	criteria provided, single submitter	clinical testing	The PCNT c.5582C>T variant is predicted to result in the amino acid substitution p.Ala1861Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.