Submissions for variant NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)

dbSNP: rs747134711

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237217	SCV001960933	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-18	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) 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: PM2 - PopMax MAF = 0.00003266 (0.003266%) in East Asian (gnomAD v2.1.1). PP3 - REVEL: 0,857. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling validated clinical criteria for FH from different labs. PS3_supporting - PMID: 9409298 - Level 3 assay - study on htz patient's cultured lymphoblasts, immunoblotting + I125-LDL assay, no precursor detectable, degradation of 125I-LDL 63%. ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)).
LDLR-LOVD, British Heart Foundation	RCV000237217	SCV000295715	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237217	SCV000484688	uncertain significance	Hypercholesterolemia, familial, 1	2019-08-22	criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237217	SCV000503426	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Other mutation at same codon/Software predictions: Conflicting
Color Diagnostics, LLC DBA Color Health	RCV001182067	SCV001347390	likely pathogenic	Familial hypercholesterolemia	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Phe598Leu in the mature protein) replaces phenylalanine with leucine at codon 619 in the LDLR type B repeat 6 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using lymphocytes from a heterozygous individual affected with familial hypercholesterolemia have shown that this variant causes a 60-65% residual level of LDLR activity and expression (PMID: 9409298). This variant has been reported in several heterozygous individuals affected with familial hypercholesterolemia (PMID: 9409298, 17094996, 17539906, 20236128, 29720182, 34998859; Color internal data; ClinVar SCV000484688.2, SCV000503426.1, SCV001960933.1). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34998859). This variant has been identified in 1/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Phe619Ser and p.Phe619Cys, are considered to be disease-causing (ClinVar variation ID: 252084 and 252085), suggesting that phenylalanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001182067	SCV002074239	likely pathogenic	Familial hypercholesterolemia	2022-01-13	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1855T>C (p.Phe619Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251492 control chromosomes. c.1855T>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Sun_1997, Tosi_2007, Taylor_2007, Paththinige_2018). Additionally, experimental studies performed on a heterozygous patient's cultured lymphoblasts showed LDL-receptor expression and activity was reduced to around 60% of wild-type, consistent with damaging effect of the variant (Sun_1997). The variant was classified as likely pathogenic by ClinGen Familial Hypercholesterolemia Expert Panel for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (3) and likley pathogenic (1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001182067	SCV003442677	pathogenic	Familial hypercholesterolemia	2022-11-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe619 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20809525). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 252083). This variant is also known as Phe598Leu. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9544745, 17539906; Invitae). This variant is present in population databases (rs747134711, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 619 of the LDLR protein (p.Phe619Leu).
GeneDx	RCV003238749	SCV003936528	likely pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies using a heterozygous patient's cultured lymphoblasts reveal reduced LDL receptor activity (Sun et al., 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel; Also known as p.F598L; This variant is associated with the following publications: (PMID: 17094996, 29720182, 9409298, 17539906, 20236128, 9544745)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237217	SCV000606541	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research