Submissions for variant NM_006031.6(PCNT):c.4675A>T (p.Met1559Leu)

gnomAD frequency: 0.00074  dbSNP: rs180775012

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597273	SCV000704938	uncertain significance	not provided	2017-01-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765509	SCV000896815	uncertain significance	Microcephalic osteodysplastic primordial dwarfism type II	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000765509	SCV001300985	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000765509	SCV001471956	likely benign	Microcephalic osteodysplastic primordial dwarfism type II	2023-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000597273	SCV001765623	likely benign	not provided	2021-06-10	criteria provided, single submitter	clinical testing
Invitae	RCV000597273	SCV002138372	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1559 of the PCNT protein (p.Met1559Leu). This variant is present in population databases (rs180775012, gnomAD 0.2%), 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: 499448). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV003915710	SCV004732024	likely benign	PCNT-related condition	2022-04-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000597273	SCV001798503	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000597273	SCV001965014	likely benign	not provided		no assertion criteria provided	clinical testing