Submissions for variant NM_000439.5(PCSK1):c.1918A>G (p.Thr640Ala)

gnomAD frequency: 0.00157  dbSNP: rs139453594

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503873	SCV000596381	uncertain significance	not specified	2016-02-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001158034	SCV001319648	uncertain significance	Obesity due to prohormone convertase I deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001700397	SCV003244922	likely benign	not provided	2023-12-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001158034	SCV003925137	uncertain significance	Obesity due to prohormone convertase I deficiency	2022-03-15	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700397	SCV001920857	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000503873	SCV001930697	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001700397	SCV001969180	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409704	SCV004113731	uncertain significance	PCSK1-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The PCSK1 c.1918A>G variant is predicted to result in the amino acid substitution p.Thr640Ala. This variant was reported to be associated with high body mass index (BMI) (Ayers et al. 2018. PubMed ID: 29726959). This variant was also reported in one individual with hypothalamic amenorrhea and in two control individuals from a cohort study of women with hypothalamic amenorrhea (Delaney et al. 2020. PubMed ID: 32870266). However, in vitro functional studies show similar activity to wild type (Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747; Folon et al. 2023. PubMed ID: 36822744), and it is also documented in the general population with an allele frequency up to 0.45% in Ashkenazi Jewish populations. These data indicate that this variant may confer a genetic risk for obesity but likely does not constitute a pathogenic variant for Mendelian disease. Taken together, although we suspect this variant may be benign for Mendelian disease, at this time its clinical significance is uncertain.