Submissions for variant NM_174936.4(PCSK9):c.464C>T (p.Pro155Leu)

gnomAD frequency: 0.00001  dbSNP: rs775429340

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000771323	SCV000903590	uncertain significance	Familial hypercholesterolemia	2022-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 155 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown that p.Pro155Ala abolished autocatalytic processing of the PCSK9 protein, suggesting that the variant may have LDL-C-lowering effect in vivo (PMID: 15358785). This variant been reported in a small Pakistani family affected with familial hypercholesterolemia and did not show segregation with lipid levels (PMID: 23535506). This variant has been identified in 22/251446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793123	SCV000932463	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 155 of the PCSK9 protein (p.Pro155Leu). This variant is present in population databases (rs775429340, gnomAD 0.07%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 23535506). ClinVar contains an entry for this variant (Variation ID: 627676). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PCSK9 protein function with a negative predictive value of 80%. 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.
All of Us Research Program, National Institutes of Health	RCV000793123	SCV004842214	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 155 of the PCSK9 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that p.Pro155Ala abolished autocatalytic processing of the PCSK9 protein, suggesting that the variant may have LDL-C-lowering effect in vivo (PMID: 15358785). This variant been reported in a small Pakistani family affected with familial hypercholesterolemia and did not show segregation with lipid levels (PMID: 23535506). This variant has also been identified in 22/251446 chromosomes (21/30616 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant causes disease, available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.