ClinVar

Description

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 501 of the PROS1 protein (p.Ser501Pro). This variant is present in population databases (rs121918472, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This variant is known as the Heerlen variant, also reported as Ser460Pro. This variant has been reported in several individuals with type III protein S deficiency and it segregates with disease in multiple families but some carriers are unaffected (PMID: 7579448, 1547381, 12960605, 24119292). The pathogenicity of this variant is much debated in the literature with reports that argue for a pathogenic classification, a benign polymorphism as well as a modifier that works in synergy with other genetic factors. It has also been observed to segregate with disease in related individuals. This variant has been classified as a polymorphism in some reports because it is present at a similar frequency in controls as well as affected individuals (PMID: 2143091, 24014240) and it has been reported in unaffected family members (PMID: 15147381). In contrast, several studies report a statistically significant increase in the Heerlen allele frequency in individuals with low protein S levels and/or venous thrombosis (PMID: 8765219, 7579448, 10669162, 28374852). In addition, individuals homozygous for Heerlen have been reported to have lower protein S levels and a more severe type I form compared to individuals that are heterozygous (PMID: 10887114, 10669162). Finally, several reports suggest that the Heerlen variant shows synergy with other genetic risks for thrombosis such as Factor V Leiden and/or APC (activated protein C) variants (PMID: 8765219, 10669162, 20880255, 24365770). One functional study reports a synergy with Factor V Leiden mutation and a reduced capacity for the Heerlen variant to act as a co-factor for APC (PMID: 10887114). ClinVar contains an entry for this variant (Variation ID: 13316). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PROS1 protein function. In conclusion, there is evidence to support increased risk for protein S deficiency in heterozygous individuals and homozygous individuals show a more severe deficiency, although this variant has also been reported in unaffected family members and in control individuals. There is also evidence to support that the Heerlen variant alone has a mild effect but acts in synergy with other genetic factors. Because there is support for both a pro-pathogenic and a pro-benign effect, this sequence change has been classified as Uncertain Significance.