Submissions for variant NM_000527.5(LDLR):c.1323C>G (p.Ile441Met)

dbSNP: rs5933

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238156	SCV002506366	uncertain significance	Hypercholesterolemia, familial, 1	2022-01-17	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PM5) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.769. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID: 251782) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.
LDLR-LOVD, British Heart Foundation	RCV000238156	SCV000295363	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238156	SCV000503332	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238156	SCV000583820	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191368	SCV001359164	likely pathogenic	Familial hypercholesterolemia	2019-03-22	criteria provided, single submitter	clinical testing	This variant (also known as p.Ile420Met in the mature protein and as FH Roen) is a missense variant located in the first LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental functional study has shown that patient cells carrying this variant have 5-15% LDLR activity. These cells were from a French individual diagnosed with familial hypercholesterolemia that was apparently compound heterozygous with an unknown second allele (PMID: 1301956). Two other variants at the same amino acid position (p.Ile441Asn and p.Ile441Thr) have been detected in several patients with hypercholesterolemia and segregated in affected family members, and both variants have been shown to be functionally defective (PMID: 1301956, 25741862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.