Submissions for variant NM_000527.5(LDLR):c.979C>T (p.His327Tyr)

gnomAD frequency: 0.00006  dbSNP: rs747507019

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238224	SCV004022469	uncertain significance	Hypercholesterolemia, familial, 1	2022-07-22	reviewed by expert panel	curation	NM_000527.5(LDLR):c.979C>T (p.His327Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows: PM2 - Variant is found in South Asian (gnomAD v2.1.1 (Popmax MAF = 0.0004900 (0.049%), total alleles number = 15), gnomAD v4.0.0 (Popmax MAF = 0.0006492 (0.06492%), total alleles number = 56)). Variant is absent from other populations in gnomAD v2.1.1 and is found in only 1 case from Remaining population in gnomAD v4.0.0 (Popmax MAF = 0.00001656 ( 0.001656%)). We assume founder effect due to isolated occurrence in the South Asian population. For this reason, we excluded the SA population from PM2 assessment. PP3 - REVEL = 0.958. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. PS4_Supporting - Variant meets PM2 and is identified in 3 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria in PMID: 9259195 (Day et al., 1997), UK; 1 case with DLCN criteria>=6 in PMID: 11810272 (Fouchier et al., 2001), The Netherlands).
LDLR-LOVD, British Heart Foundation	RCV000238224	SCV000295124	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238224	SCV000484756	likely pathogenic	Hypercholesterolemia, familial, 1		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	RCV000238224	SCV000503272	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055792	SCV000697257	uncertain significance	not specified	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.979C>T (p.His327Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250950 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.2e-05 vs 0.0013), allowing no conclusion about variant significance. c.979C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Day_1997, Gill_2021, Arrobas Vililla_2022, Diboun_2022, Ribert_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Two independent functional studies reveal that this variant results in a molecular gain-of-function, i.e. enhanced LDLR binding to PCSK9. This increased affinity of PCSK9 to the LDLR would in turn lead to enhanced LDLR destruction, decreased plasma LDL-C clearance, and hypercholesterolemia. However, due to the lack of strong clinical data, this variant can not be definitively classified as pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 9259195, 11810272, 15199436, 23833242, 27050191, 19001363, 19224862, 11313767, 33303402, 36105085, 35910211, 35047021). ClinVar contains an entry for this variant (Variation ID: 251583). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248905	SCV001422595	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.His327Tyr variant in LDLR has been reported in at least 4 individuals with familial hypercholesterolemia (PMID: 9259195, 11810272, 15199436, 23833242), and has been identified in 0.05% (15/30610) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747507019). This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251583). In vitro functional studies provide some evidence that the p.His327Tyr variant may slightly impact protein function (PMID: 19224862, 19001363). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_supporting, PS3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248905	SCV003519744	uncertain significance	Familial hypercholesterolemia	2022-03-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 327 of the LDLR protein (p.His327Tyr). This variant is present in population databases (rs747507019, gnomAD 0.05%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195, 15199436, 23833242, 27765764, 33303402, 33740630). This variant is also known as p.His306Tyr. ClinVar contains an entry for this variant (Variation ID: 251583). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LDLR function (PMID: 19001363, 19224862, 23675525). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004639191	SCV005135998	uncertain significance	Cardiovascular phenotype	2024-03-19	criteria provided, single submitter	clinical testing	The p.H327Y variant (also known as c.979C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 979. The histidine at codon 327 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Day IN et al. Hum Mutat, 1997;10:116-27; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Kusters DM et al. J Lipid Res, 2013 Sep;54:2543-9; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Rimbert A et al. Front Genet, 2021 Jan;12:809256; Arrobas Velilla T et al. Front Genet, 2022 Aug;13:971651; Diboun I et al. Front Genet, 2022 Jul;13:927504). In vitro study noted this alteration may impact protein function (Dong H et al. J Lipid Res, 2017 Feb;58:364-374). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238224	SCV000606288	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001248905	SCV001460261	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing