Submissions for variant NM_000439.5(PCSK1):c.772C>A (p.Pro258Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002640738	SCV003525886	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects PCSK1 function (PMID: 23562752, 26207343). 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"). This missense change has been observed in individual(s) with clinical features of PCSK1-related conditions (PMID: 23562752). This variant is present in population databases (rs560420109, gnomAD 0.06%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the PCSK1 protein (p.Pro258Thr).
Neuberg Centre For Genomic Medicine, NCGM	RCV004764808	SCV005374756	uncertain significance	Obesity due to prohormone convertase I deficiency		criteria provided, single submitter	clinical testing	The observed missense c.772C>A(p.Pro258Thr) variant in PCSK1 gene has been reported in compound heterozygous state in individuals affected with PCSK1 related disorder (Martín MG, et. al., 2013). Experimental studies have shown that this missense change affects PCSK1 function (Martín MG, et. al., 2013; Blanco EH, et. al., 2015). This variant is present with an allele frequency of 0.006% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain significance. Multiple lines of computational evidence (Polyphen -Probably Damaging, SIFT - Damaging and MutationTaster -disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid in PCSK1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 258 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). The same variant in PCSK1 gene was identified in heterozygous state in the spouse [RUBINABANO SINDHI, Id: 30607400433].
PreventionGenetics, part of Exact Sciences	RCV003953969	SCV004776358	uncertain significance	PCSK1-related disorder	2023-10-30	no assertion criteria provided	clinical testing	The PCSK1 c.772C>A variant is predicted to result in the amino acid substitution p.Pro258Thr. This variant was reported in the homozygous state in an individual with proprotein convertase 1/3 deficiency in the presence of another uncertain homozygous variant, and in vitro functional analysis showed partial loss of enzymatic function (Martín et al 2013. PubMed ID: 23562752). This variant was also observed in a cohort of individuals with obesity, and in vitro functional studies showed inconclusive evidence of loss of function (Supplemental Data Set, Shah et al 2023. PubMed ID: 36864747). This variant is reported in 0.049% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-95748132-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.