rs730882101

Variant names:

• chr19-11113569-T-A
• rs730882101
• NM_000527.5:c.1393T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA023482/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:10 B:1 O:1
• Conservation: PhyloP100: 3.95
• Publications: 2 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1393T>A	p.Tyr465Asn	missense	Exon 10 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1393T>A	p.Tyr465Asn	missense	Exon 10 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1270T>A	p.Tyr424Asn	missense	Exon 9 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1393T>A	p.Tyr465Asn	missense	Exon 10 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1651T>A	p.Tyr551Asn	missense	Exon 10 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1393T>A	p.Tyr465Asn	missense	Exon 10 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251026 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461728 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 727162

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:3 Benign:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Sep 05, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM2_P, PP3; Variant was found in heterozygous state. Patient also carried NM_000527.5:c.1294C>G heterozygously.

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: 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

Familial hypercholesterolemia Uncertain:3

Apr 24, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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, 32770674). ClinVar contains an entry for this variant (Variation ID: 183114). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. 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.

Aug 19, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:1 Other:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM2

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

not specified Uncertain:1

Sep 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

LDLR-related disorder Uncertain:1

Nov 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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.

Cardiovascular phenotype Uncertain:1

May 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.82
Sift	Benign	0.045	D
Sift4G	Benign	0.15	T
Polyphen		0.015	B
Vest4		0.51
MutPred		0.52		Gain of disorder (P = 0.0173)
MVP		1.0
MPC		0.39
ClinPred		0.15	T
GERP RS		0.71
Varity_R		0.26
gMVP		0.94
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882101; hg19: chr19-11224245;