Submissions for variant NM_000527.5(LDLR):c.1A>T (p.Met1Leu)

dbSNP: rs879254382

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238419	SCV001960929	pathogenic	Hypercholesterolemia, familial, 1	2022-03-17	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1A>T (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS1, PS3, PM2, PVS1_Moderate, PP4 and PS4_Supporting 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: PS1 - One more missense variant that leads to the same amino acid change: (1)NM_000527.5(LDLR):c.1A>C (p.Met1Leu) (ClinVar ID 250966) - Pathogenic by these guidelines --- variant is classified as Pathogenic, so PS1 is Met. PS3 - Level 1 (and other levels) FS: Graça et al., 2021 (PMID 34572405) Heterologous cells (CHO), FACS, luciferase and microscopy assays: FACS: 10% cell surface LDLR, 3% binding and 8% uptake; luciferase : 1% luciferase construct activity; microscopy: 5-10% LDLR expression and 5-10% LDLR activity. --- functional study in heterologous cells results in expression, binding and uptake less than 70% of wild-type, so PS3 is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PVS1_moderate - Variant is in initiation codon, so PVS1_Moderate is Met. PS4_supporting - Variant meets PM2 and was identified in: - 1 index case with DLCN score above 6 from University of British Columbia, Canada; - 1 index case with Simon-Broome criteria of possible FH 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; - 1 index case with Simon-Broome criteria of possible FH (Inclusion: LDL-C level>95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, and a family history of hypercholesterolemia and cardiovascular disease) from PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; - 1 index case with Simon-Broome criteria of at least possible FH from PMID: 17094996 (Tosi et al., 2007), UK. --- 4 cases, so PS4_Supporting is Met PP4 - Variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is Met.
LDLR-LOVD, British Heart Foundation	RCV000238419	SCV000294407	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV001220717	SCV001392726	pathogenic	Familial hypercholesterolemia	2023-08-08	criteria provided, single submitter	clinical testing	Disruption of the initiator codon has been observed in individual(s) with familial hypercholesterolemia (PMID: 8831933, 21382890, 23680767). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). ClinVar contains an entry for this variant (Variation ID: 250968). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the LDLR mRNA. The next in-frame methionine is located at codon 264.
New York Genome Center	RCV000238419	SCV002764528	pathogenic	Hypercholesterolemia, familial, 1	2020-12-16	criteria provided, single submitter	clinical testing	The heterozygous c.1A>T (p.Met1?) variant identified in the LDLR gene affects the translation-initiator Methionine and is predicted to abolish the synthesis of a normal LDLR molecule. The variant has been reported in multiple individuals affected with familial hypercholesterolemia [PMID: 8831933, 21382890, and more]. The variant is reported in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [VarID:250968]. The c.1A>T (p.Met1?) variant is absent from the gnomAD database indicating it is an extremely rare allele in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools. Based on the available evidence, the c.1A>T (p.Met1?) variant identified in the LDLR gene is reported as Pathogenic.
Revvity Omics, Revvity	RCV000238419	SCV003827762	pathogenic	Hypercholesterolemia, familial, 1	2022-08-03	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238419	SCV000605992	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research