rs730882102

Variant names:

• chr19-11113590-G-A
• rs730882102
• NM_000527.5:c.1414G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11113590-G-A
• chr19-11113590-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP4 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1414G>A (p.Asp472Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001120 (0.0112%) in Remaining exomes+genomes (gnomAD v4.1.0); PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (ClinVar ID 183116) -Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines; BP4 - REVEL = 0.318, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create AG. Variant is not predicted to alter splicing; PP4 - Variant meets PM2. Identified in at least 1 index case fulfilling Japanese Atherosclerosis Society criteria for FH from PMID 36229376, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404085864/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:5
• Conservation: PhyloP100: 2.58

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1414G>A	p.Asp472Asn	missense_variant	Exon 10 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1414G>A	p.Asp472Asn	missense_variant	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461740 Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12 AN XY: 727182

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM2, PM5, PS4:Moderate -

-

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Uncertain:2

Jan 31, 2025

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.1414G>A (p.Asp472Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001120 (0.0112%) in Remaining exomes+genomes (gnomAD v4.1.0); PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (ClinVar ID 183116) -Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines; BP4 - REVEL = 0.318, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create AG. Variant is not predicted to alter splicing; PP4 - Variant meets PM2. Identified in at least 1 index case fulfilling Japanese Atherosclerosis Society criteria for FH from PMID 36229376, after alternative causes of high cholesterol were excluded. -

Aug 06, 2024

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 replaces aspartic acid with asparagine at codon 472 of the LDLR protein. This variant is also known as p.Asp451Asn in the mature protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 35626767, 36329474) and in one individual affected with primary dyslipidemia (PMID: 29572815). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Asp472Asn, is considered to be disease-causing (Clinvar variation ID: 183116), indicating that aspartic acid at this position is important for LDLR protein function. 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. -

not specified Uncertain:1

Dec 03, 2021

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.1414G>A (p.Asp472Asn) results in a conservative amino acid change located in the LDLR class B repeat domain (IPR000033; InterPro) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251206 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1414G>A has been reported in the literature in an individual affected with hypercholesterolemia, and the authors of this study classified the variant as likely pathogenic, however no information was provided for independent evaluation (Marmontel_2018). Therefore, these data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different missense affecting the same residue, c.1414G>T (p.Asp472Tyr), is classified as likely pathogenic by our laboratory. In addition, missense changes affecting nearby residues (e.g. Y465C, T467I, S470C, I473N, A475V) have been reported in individuals affected with hypercholesterolaemia (HGMD), suggesting that this protein region may be clinically significant. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cardiovascular phenotype Uncertain:1

Apr 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D472N variant (also known as c.1414G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1414. The aspartic acid at codon 472 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individuals from cohorts with features consistent with familial hypercholesterolemia (Marmontel O et al. Clin Genet. 2020 Dec;98(6):589-594; Gandhi GD et a. J Transl Med. 2022 Nov;20(1):502). This amino acid position is 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. -

Familial hypercholesterolemia Uncertain:1

Mar 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;.;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.5	L;.;.;.;.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.57	T;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T
Polyphen		0.011	B;.;.;.;.;.
Vest4		0.14
MutPred		0.64		Loss of catalytic residue at D472 (P = 0.0747);Loss of catalytic residue at D472 (P = 0.0747);.;.;.;Loss of catalytic residue at D472 (P = 0.0747);
MVP		1.0
MPC		0.23
ClinPred		0.41	T
GERP RS		2.5
Varity_R		0.13
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882102; hg19: chr19-11224266;