Submissions for variant NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro)

dbSNP: rs879254851

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237865	SCV005903159	likely pathogenic	Hypercholesterolemia, familial, 1	2025-01-31	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4_Moderate, PM2, PM3, PP1_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0). So, PM2 is met. PP3: REVEL=0.883. It is above 0.75, so PP3 is met. PS4_Moderate, PP4: Variant meets PM2 and is identified in 9 unrelated index cases (2 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 5 cases with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille, France, published on ClinVar; 1 case with possible/definite FH by Simon-Broome criteria in PMID 33269076 (Miroshnikova et al., 2021); 1 case with DLCN score 9 in PMID 9763532 (Mak et al., 1998)). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France: 4 affected family members have the variant. PM3: A homozygous proband is reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies with LDL of 860 mg/dL.
LDLR-LOVD, British Heart Foundation	RCV001350143	SCV000295337	likely pathogenic	Familial hypercholesterolemia	2016-03-25	criteria provided, single submitter	literature only	Re-evaluation of ACMG classification, scoring: PM2, PM3, PP1_supporting, PS4_supporting and PP3. PM3 and PP1_supporting criteria were supported by a submission to ClinGen Variant interface by Ana Medeiros.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237865	SCV000583815	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001350143	SCV001544523	likely pathogenic	Familial hypercholesterolemia	2022-05-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 426 of the LDLR protein (p.Leu426Pro). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9763532, 25775905, 33269076; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu426 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 28353356), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 251763). This variant is also known as L405P.
Ambry Genetics	RCV002446478	SCV002683170	pathogenic	Cardiovascular phenotype	2019-11-08	criteria provided, single submitter	clinical testing	The p.L426P pathogenic mutation (also known as c.1277T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1277. The leucine at codon 426 is replaced by proline, an amino acid with similar properties. This mutation (described as legacy p.L405P) has been reported in an individual with familial hypercholesterolemia (FH) (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on internal structural assessment, this alteration disrupts the beta-propeller domain of LDLR (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this position, p.L426R, was also reported in an FH cohort, suggesting this position is a hotspot (Rubba P et al. Eur J Prev Cardiol, 2017 07;24:1051-1059). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV000237865	SCV002761840	likely pathogenic	Hypercholesterolemia, familial, 1	2022-07-06	criteria provided, single submitter	clinical testing