ClinVar Miner

Submissions for variant NM_000439.5(PCSK1):c.375G>A (p.Met125Ile)

gnomAD frequency: 0.00018  dbSNP: rs146545244
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001156478 SCV001317977 uncertain significance Obesity due to prohormone convertase I deficiency 2017-08-25 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.
GeneDx RCV001567232 SCV001790882 uncertain significance not provided 2020-03-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22210313, 27187081)
Labcorp Genetics (formerly Invitae), Labcorp RCV001567232 SCV003271387 uncertain significance not provided 2022-08-27 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 125 of the PCSK1 protein (p.Met125Ile). This variant is present in population databases (rs146545244, gnomAD 0.03%). This missense change has been observed in individual(s) with obesity (PMID: 22210313). ClinVar contains an entry for this variant (Variation ID: 906974). 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. Experimental studies have shown that this missense change affects PCSK1 function (PMID: 22210313). 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 RCV003938523 SCV004748002 uncertain significance PCSK1-related disorder 2024-08-26 no assertion criteria provided clinical testing The PCSK1 c.375G>A variant is predicted to result in the amino acid substitution p.Met125Ile. This variant has been reported in a heterozygous state in individuals with obesity (Creemers et al. 2012. PubMed ID: 22210313; Pickett et al. 2013. PubMed ID: 23383060). Creemers et al. showed that the c.375G>A variant leads to partial loss of PCSK1 activity, and carriers of these types of variants had ~ 9-fold increased risk of obesity when compared to controls. Another functional study also showed strong evidence of loss of function (Table 3 and Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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