Submissions for variant NM_006031.6(PCNT):c.3581C>T (p.Ala1194Val)

gnomAD frequency: 0.00038  dbSNP: rs138254119

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147116	SCV000194476	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2013-10-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000147116	SCV000436984	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.
Fulgent Genetics, Fulgent Genetics	RCV000147116	SCV000896812	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2021-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV001849988	SCV002121744	uncertain significance	not provided	2022-09-27	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 1194 of the PCNT protein (p.Ala1194Val). This variant is present in population databases (rs138254119, 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: 159591). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002514826	SCV003678572	uncertain significance	Inborn genetic diseases	2021-09-01	criteria provided, single submitter	clinical testing	The c.3581C>T (p.A1194V) alteration is located in exon 18 (coding exon 18) of the PCNT gene. This alteration results from a C to T substitution at nucleotide position 3581, causing the alanine (A) at amino acid position 1194 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003415977	SCV004116855	uncertain significance	PCNT-related condition	2023-11-27	criteria provided, single submitter	clinical testing	The PCNT c.3581C>T variant is predicted to result in the amino acid substitution p.Ala1194Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.