19-11113375-C-G

Variant names:

• chr19-11113375-C-G
• rs368708058
• NM_000527.5:c.1284C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1284C>G (p.Asn428Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting 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: Variant is absent from gnomAD (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 index cases who fulfill criteria for FH (1 case with total cholesterol >8 mmol/L and family history of hypercholesterolemia or classical clinical stigmata of FH from PMID 11857755 (Bunn et al., 2002), New Zealand; 1 case with total cholesterol >90th percentile and clinical features of FH or family history of early CHD from PMID 11845603 (Vergotine et al., 2001), South Africa; 1 case with DLCN score >=6 from PMID 11810272 (Fouchier et al., 2001), the Netherlands; 1 case with LDL >95th percentile, plus two of: presence of xanthomata, CAD in proband or family history of CAD or high LDL, from PMID 11668640 (Garcia-Garcia et al., 2001) Spain; 1 case with LDLC 6.5 mmol/L, presence of xanthomas, and history of angioplasty or bypass surgery from PMID 11005141 (Khoo et al., 2000), Malaysia. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585385/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:6 U:2
• Conservation: PhyloP100: -0.914
• Publications: 7 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 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1284C>G	p.Asn428Lys	missense	Exon 9 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1284C>G	p.Asn428Lys	missense	Exon 9 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1161C>G	p.Asn387Lys	missense	Exon 8 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.1284C>G	p.Asn428Lys	missense	Exon 9 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1542C>G	p.Asn514Lys	missense	Exon 9 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1284C>G	p.Asn428Lys	missense	Exon 9 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461714 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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: 53250

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 29

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	Familial hypercholesterolemia (4)
2	1	-	Hypercholesterolemia, familial, 1 (3)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.8
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.7	L
PhyloP100		-0.91
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	P
Vest4		0.80
MutPred		0.90		Gain of methylation at N428 (P = 0.0236)
MVP		1.0
MPC		0.70
ClinPred		1.0	D
GERP RS		-3.7
Varity_R		0.92
gMVP		0.98
Mutation Taster		=0/100	disease causing

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: rs368708058; hg19: chr19-11224051;