rs368889457

chr19-11113679-G-Achr19-11113679-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000527.5(LDLR):c.1503G>A(p.Ala501=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. A501A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:8 B:3
• Conservation: PhyloP100: -2.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1503G>A	p.Ala501=	synonymous_variant	10/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1503G>A	p.Ala501=	synonymous_variant	10/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251456 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135908

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461864 Hom.: 0 Cov.: 35 AF XY: 0.0000289 AC XY: 21 AN XY: 727238

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74432

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000332 Hom.: 0

Bravo AF: 0.000147

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:8 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 27, 2022	The NM_000527.5(LDLR):c.1503G>A (p.Ala501=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.0002403 (0.02403%) in African/African American population exomes/genomes (gnomAD version). PP3: No REVEL score, splicing evaluation required. Functional data on splicing not available. B). Variant is exonic and at least 50bp upstream from canonical donor site and creates AG MES scores: de novo variant = 9.20; canonical acceptor = 6.76. Ratio de novo variant/canonical acceptor = 9.20/6.76 = 1.36 --- it is above 0.9 PP4: variant meets PM2, identified in 1 FH index case from PMID: 20145306 with WHO criteria, after alternative causes of high cholesterol were excluded. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.1503G>A variant in LDLR has been reported in 4 individuals, including one Polish individual, with Familial Hypercholesterolemia (PMID: 20145306, Variation ID: 251876), and has been identified in 0.02403% (6/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368889457). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 251876). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple missense variants in the same region as c.1503G>A have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 251867, 251868, 251870, 265903, 251874, 251873, 251877). 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, PM1_Supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction tools suggest that this variant may impact RNA splicing through creation of a novel acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 30293936). This variant has been identified in 11/282836 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. -

Familial hypercholesterolemia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction tools suggest that this variant may impact RNA splicing through creation of a novel acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 30293936). This variant has been identified in 11/282836 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2022	This sequence change affects codon 501 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs368889457, gnomAD 0.03%). This variant has been observed in individual(s) with definite or suspected hypercholesterolemia (PMID: 20145306, 22881376). ClinVar contains an entry for this variant (Variation ID: 251876). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 19, 2020	- -

not specified Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2023	Variant summary: LDLR c.1503G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251456 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1503G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Chmara 2010, Martin-Campos 2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 22881376, 30293936, 32719484). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6), likely benign (n=1), or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2023

The c.1503G>A variant (also known as p.A501A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1503. This nucleotide substitution does not change the alanine at codon 501. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Chmara M et al. J Appl Genet, 2010;51:95-106; Martín-Campos JM et al. J Clin Lipidol, 2018 Sep;12:1452-1462). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.64		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368889457; hg19: chr19-11224355;