Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237536 | SCV002506393 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-04-21 | reviewed by expert panel | curation | The NM_000527.5 (LDLR): c.1856T>C (p.Phe619Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1) PP3 Met: REVEL = 0.832, which is above the threshold for 0.75. PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Moderate Met: Variant meets PM2, and is identified in 6 unrelated index cases who fulfil DLCN criteria for FH from different labs. Two index cases reported from U4M – Lille University &CHRU Lille, University de Lille – CHRU de Lille (SCV000583896.1). Four French index cases reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, (SCV000503427.1, PMID20809525). There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>G (p.Phe619Cys), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met. |
| LDLR- |
RCV000237536 | SCV000295716 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000237536 | SCV000503427 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / previously described in association with FH and Other mutation at same codon/software prediction damaging |
| U4M - |
RCV000237536 | SCV000583896 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001854906 | SCV002126767 | pathogenic | Familial hypercholesterolemia | 2021-05-05 | criteria provided, single submitter | clinical testing | 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe619 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003, 29720182, 9544745), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 20809525, Invitae). ClinVar contains an entry for this variant (Variation ID: 252084). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 619 of the LDLR protein (p.Phe619Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237536 | SCV000606542 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |