rs1131692207

Variant names:

• chr19-11113588-G-A
• rs1131692207
• NM_000527.5:c.1412G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP4 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1412G>A (p.Arg471Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).BP4: REVEL = 0.412, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) does not create AG or GTC) variant is exonic and there are 2 AG nearby;#1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76;#2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76.Scores are negative, so variant is not predicted to alter splicing.PP4: Variant meets PM2 and is identified in at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404085845/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 B:1
• Conservation: PhyloP100: 0.580
• 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 2 ACMG points.

• PM2: 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.1412G>A	p.Arg471Lys	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.1412G>A	p.Arg471Lys	missense_variant	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

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

American (AMR) AF: 0.00 AC: 0 AN: 44710

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 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.1412G>A (p.Arg471Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). BP4: REVEL = 0.412, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG or GT C) variant is exonic and there are 2 AG nearby; #1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76; #2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76. Scores are negative, so variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	5.1
DANN	Benign	0.84
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.54	T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	-1.1	N;.;.;.;.;N
PhyloP100		0.58
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.17	N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.054
MutPred		0.46		Gain of ubiquitination at R471 (P = 0.0192);Gain of ubiquitination at R471 (P = 0.0192);.;.;.;Gain of ubiquitination at R471 (P = 0.0192);
MVP		0.99
MPC		0.21
ClinPred		0.034	T
GERP RS		-2.9
Varity_R		0.24
gMVP		0.86
Mutation Taster		=58/42	disease causing (ClinVar)

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: rs1131692207; hg19: chr19-11224264;