Submissions for variant NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn)

gnomAD frequency: 0.00001  dbSNP: rs730882101

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237809	SCV004022456	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 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 = 0.00001764 in European non-Finnish exomes (gnomAD v2.1.1) PP3: REVEL = 0.82
LDLR-LOVD, British Heart Foundation	RCV000237809	SCV000295410	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782265	SCV000697196	uncertain significance	not specified	2024-09-06	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1393T>A (p.Tyr465Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-06 in 264244 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1393T>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia with or without myocardiac infarction and at least two pts also carried a second variant without unknown phase or the pathogenicity of the second variant (Leren_2004, Do_2015, Thormaehlen_2015, Alieva_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 15199436, NOT_FOUND, 25487149, 38245461). ClinVar contains an entry for this variant (Variation ID: 183114). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041965	SCV001205619	uncertain significance	Familial hypercholesterolemia	2021-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 465 of the LDLR protein (p.Tyr465Asn). This variant is present in population databases (rs730882101, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 15199436, 25487149, 25647241, 28964736). ClinVar contains an entry for this variant (Variation ID: 183114). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001041965	SCV001353774	uncertain significance	Familial hypercholesterolemia	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Tyr444Asn in the mature protein) replaces tyrosine with asparagine at codon 465 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). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 29396260, 32770674). This variant has been identified in 2/251026 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002390393	SCV002700108	uncertain significance	Cardiovascular phenotype	2023-05-02	criteria provided, single submitter	clinical testing	The p.Y465N variant (also known as c.1393T>A), located in coding exon 10 of the LDLR gene, results from a T to A substitution at nucleotide position 1393. The tyrosine at codon 465 is replaced by asparagine, an amino acid with dissimilar properties. This variant (also referred to as Y444N) has been detected in hypercholesterolemia and myocardial infarction cohorts; however, in several cases, clinical detail was limited and/or the variant co-occurred with other variants in the LDLR gene, complicating interpretation of the impact of this variant alone (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Do R et al. Nature. 2015 Feb;518(7537):102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Rieck L et al. Clin Genet. 2020 Nov;98(5):457-467). One in vitro assay reported this variant to be non-disruptive to LDL uptake; however, additional evidence is needed to confirm this finding (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000237809	SCV004820312	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Tyr444Asn in the mature protein) replaces tyrosine with asparagine at codon 465 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). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 29396260, 32770674). This variant has been identified in 2/251026 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute of Immunology and Genetics Kaiserslautern	RCV000237809	SCV005382123	uncertain significance	Hypercholesterolemia, familial, 1	2022-09-05	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2_P, PP3; Variant was found in heterozygous state. Patient also carried NM_000527.5:c.1294C>G heterozygously.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161986	SCV000189561	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237809	SCV000606413	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001041965	SCV002086421	uncertain significance	Familial hypercholesterolemia	2020-08-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895080	SCV004715874	uncertain significance	LDLR-related disorder	2023-11-25	no assertion criteria provided	clinical testing	The LDLR c.1393T>A variant is predicted to result in the amino acid substitution p.Tyr465Asn. This variant has also been reported in individuals with hypercholesterolemia and in controls in different reports (Leren et al. 2004. PubMed ID: 15199436; Thormaehlen et al. 2015. PubMed ID: 25647241; Do et al. 2015. PubMed ID: 25487149). It was also found in one individual who harbored the c.1294C>G (p.Leu432Val) variant that is also found in this patient, and it was suggested that together the two variants may form a hypomorphic allele, but further studies to confirm they are on the same allele were not performed (Thormaehlen et al. 2015. PubMed ID: 25647241). A different variant of the same amino acid residue defined as p.Tyr465Cys was also reported in an individual with hypercholesterolemia (Tichý et al. 2012. PubMed ID: 22698793) suggesting that substitution of amino acid p.Tyr465 may not be tolerated. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been reported in ClinVar but with interpretations of likely benign, uncertain significance, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/183114/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.