Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001255944 | SCV004022470 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.980A>C (p.His327Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755 The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.954 PP4 - Variant meet PM2. PMID: 31345425 (Trinder et al., 2019), Canada - 1 case with clinical Dutch Lipid Clinic Network Criteria score >= 6. |
Color Diagnostics, |
RCV001175869 | SCV001339654 | uncertain significance | Familial hypercholesterolemia | 2019-10-09 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.His306Pro in the mature protein) replaces histidine with proline at codon 327 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified 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. |
Brunham Lab, |
RCV001255944 | SCV001432621 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2018-12-07 | criteria provided, single submitter | research | |
Invitae | RCV001175869 | SCV003339130 | uncertain significance | Familial hypercholesterolemia | 2022-04-15 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 327 of the LDLR protein (p.His327Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 31345425; Invitae). ClinVar contains an entry for this variant (Variation ID: 918325). 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 disruptive. 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. |