rs5932

Variant names:

• chr19-11113578-G-A
• rs5932
• NM_000527.5:c.1402G>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.1402G>A (p.Val468Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, BP4) 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 = 0.0001146 (0.012%) in non-Finnish European exomes/genomes (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in at least 1 index case (Robarts Research Institute - 1 index case w/ DLCN>=6), after alternative causes of high cholesterol have been excluded.BP4 - REVEL = 0.239. It is below 0.50. splicing evaluation required. Functional data not availableA) not on limitsB) does not create AGVariant is not predicted to alter splicing LINK:https://erepo.genome.network/evrepo/ui/classification/CA023485/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:5 O:1
• Conservation: PhyloP100: 1.76
• Publications: 8 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1402G>A	p.Val468Ile	missense	Exon 10 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1402G>A	p.Val468Ile	missense	Exon 10 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1279G>A	p.Val427Ile	missense	Exon 9 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1402G>A	p.Val468Ile	missense	Exon 10 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1660G>A	p.Val554Ile	missense	Exon 10 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1402G>A	p.Val468Ile	missense	Exon 10 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000717 AC: 18 AN: 251122 AF XY: 0.0000516

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461730 Hom.: 0 Cov.: 38 AF XY: 0.0000825 AC XY: 60 AN XY: 727166

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

American (AMR) AF: 0.0000895 AC: 4 AN: 44708

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

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

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

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000908 AC: 101 AN: 1111976

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152242 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74426

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000591 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hypercholesterolemia (3)
-	1	1	Hypercholesterolemia, familial, 1 (2)
-	1	1	not provided (3)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	9.2
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	0.33	N
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.24
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.019	B
Vest4		0.095
MVP		0.86
MPC		0.24
ClinPred		0.023	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.91
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs5932; hg19: chr19-11224254;