Submissions for variant NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr)

dbSNP: rs879254862

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237607	SCV001960927	pathogenic	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PP1_Strong, PM2, PS4_Moderate, 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: PS3 - Level 1 assay - PMID:25741862 - CHO cells, WB+FACS+CLSM, 7% low-density lipoprotein particle receptor biosynthetic process; 5% low-density lipoprotein particle binding; 10% low-density lipoprotein particle clearance. PP1_strong - 6 informative meioses in 3 families identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 9 index cases. PP3 - REVEL: 0,907. PP4 - Variant meets PM2. Variant identified in 9 index cases fulfilling specific clinical criteria for FH (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID: 20538126).
LDLR-LOVD, British Heart Foundation	RCV000237607	SCV000295362	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237607	SCV000322942	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles; 0/100 healthy control individuals
Color Diagnostics, LLC DBA Color Health	RCV000775063	SCV000909164	pathogenic	Familial hypercholesterolemia	2018-07-09	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This missense variant (also known as p.Ile420Thr in the mature protein) is located in the LDLR type B repeat 2 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. Experimental studies in CHO cells have shown that this variant causes a near complete loss of LDLR activity (~10% of normal) with retention in the endoplasmic reticulum as the precursor form (PMID: 25741862). This variant has been shown to segregate with hypercholesterolemia in 9 of 10 affected individuals from four different Portuguese families (PMID: 25741862). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Different missense variants at the same codon (p.Ile441Asn and p.Ile 441Met) are considered to be disease-causing. Based on available evidence, this variant is classified as Pathogenic.
Invitae	RCV000775063	SCV001584660	pathogenic	Familial hypercholesterolemia	2023-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 441 of the LDLR protein (p.Ile441Thr). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25741862). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251783). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11810272, 17087781, 20538126, 25741862, 27206935; Invitae). This variant is not present in population databases (gnomAD no frequency).
Revvity Omics, Revvity	RCV000237607	SCV002017113	pathogenic	Hypercholesterolemia, familial, 1	2019-05-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379061	SCV002692960	pathogenic	Cardiovascular phenotype	2020-07-30	criteria provided, single submitter	clinical testing	The p.I441T pathogenic mutation (also known as c.1322T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1322. The isoleucine at codon 441 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in multiple individuals with familial hypercholesterolemia from a range of ethnic backgrounds (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Chiu CY et al. Metab. Clin. Exp., 2005 Aug;54:1082-6; Benito-Vicente A et al. Genet. Med., 2015 Dec;17:980-8; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8). Functional studies demonstrated significantly reduced LDLR activity with precursor protein retained in the endoplasmic reticulum (Benito-Vicente A et al. Genet. Med., 2015 Dec;17:980-8). 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.
PreventionGenetics, part of Exact Sciences	RCV003401205	SCV004103745	pathogenic	LDLR-related condition	2023-09-08	criteria provided, single submitter	clinical testing	The LDLR c.1322T>C variant is predicted to result in the amino acid substitution p.Ile441Thr. This variant also described using legacy nomenclature as p.Ile420Thr, has been documented in several reports as a causative variant for Hypercholesterolemia (Fouchier et al. 2001. PubMed ID: 11810272; Medeiros et al. 2010. PubMed ID: 20828696; Benito-Vicente et al. 2015. PubMed ID: 25741862; Huang et al. 2021. PubMed ID: 33994402). Functional studies showed that this variant significantly reduced LDLR activity (Benito-Vicente et al. 2015. PubMed ID: 25741862). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237607	SCV000606392	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research