Description
The NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Moderate, PM2, PM3, PM5, 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: PS4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH: - 4 unrelated index cases with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia; - at least 1 index case with DLCN probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583646.1), France; - 8 unrelated index cases (7 with DLCN>=6 and 1 SB possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - at least 1 index case with SB criteria for FH (plasma cholesterol of >8.0 mmol/L and family histories of hypercholesterolemia and/or classical clinical stigmata of FH) from PMID 11857755 (Bunn et al., 2002), New Zeland; - 1 index case with SB criteria for FH (grossly increased plasma cholesterol concentration and the presence of xanthomata in childhood and cardiovascular involvement by puberty in the proband, together with hypercholesterolemia in both parents; this index case died at 31years, had cholesterol of 20.7mmol/L and CVD) from PMID 9026534 (Webb et al., 1996), UK so PS4 is met. PP1_moderate - Variant segregates with FH phenotype in 5 informative meiosis from 3 families: - 2 affected family members have the variant, from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 3 affected family members have the variant, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so PP1_Moderate is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in - 1 index case with phenotype of homozygous FH (cholesterol of 20.7mmol/L) and also NM_000527.5(LDLR):c.912C>G (p.Asp304Glu), Likely pathogenic by these guidelines, from PMID 9026534 (Webb et al., 1996), UK so PM3 is met PM5 - 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There is 1 variant classified as Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.957. It is above 0.75, so PP3 is met PP4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH (see PS4 for details), so PP4 is met
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
