rs121908029

Variant names:

• chr19-11105588-G-A
• rs121908029
• NM_000527.5:c.682G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11105588-G-A
• chr19-11105588-G-C
• chr19-11105588-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PS4 PP1_Strong PM1 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.682G>A (p.Glu228Lys) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PS3, PS4, PM1, PM2, PP1_Strong, PP3 and PP4 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 = 0.0001105 (0.01%) in East Asian exomes (gnomAD v2.1.1).PP3 - REVEL = 0.972. It is above 0.75.PM1 - Variant meets PM2 and is missense located in exon 4 .PS3 - Three studies contribute to PS3 attribution. One (PMID:10978268) report a level 3 assay performed on heterozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (50% LDLR activity). The second reports a level 2 assay perfomed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity).The third is permformed on Heterologous cells (COS-7). FACS, CLSM and WB results in 24% LDLR expression and 21% LDL clearance. LDLR is retained in the ER.PS4 - Variant meets PM2 and is identified in 13 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=1 Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; n=1 Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) or DLCN criteria for FH (n=1 Robarts Research Institute; n=9 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).PP1_Strong - Variant segregate with FH in 10 informatives meiosis (6 relatives positive LDL-C > 75th percentile and 4 relatives negative LDLC < 50th percentile) from 2 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo and in 1 relative positive for variant (LDL-C > 75th percentile) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP4 - Variant meets PM2 and is identified in 13 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=1 Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; n=1 Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) or DLCN criteria for FH (n=1 Robarts Research Institute; n=9 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023749/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:31 U:1
• Conservation: PhyloP100: 9.88
• Publications: 67 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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.682G>A	p.Glu228Lys	missense	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.682G>A	p.Glu228Lys	missense	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.559G>A	p.Glu187Lys	missense	Exon 3 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.682G>A	p.Glu228Lys	missense	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.940G>A	p.Glu314Lys	missense	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.682G>A	p.Glu228Lys	missense	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 247898 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454752 Hom.: 0 Cov.: 34 AF XY: 0.00000692 AC XY: 5 AN XY: 722400

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.0000224 AC: 1 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39504

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5216

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107414

Other (OTH) AF: 0.0000167 AC: 1 AN: 59992

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
18	-	-	Hypercholesterolemia, familial, 1 (18)
5	1	-	not provided (6)
5	-	-	Familial hypercholesterolemia (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.96		Gain of ubiquitination at E228 (P = 0.009)
MVP		1.0
MPC		0.86
ClinPred		0.99	D
GERP RS		5.6
PromoterAI		-0.010	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	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: rs121908029; hg19: chr19-11216264; COSMIC: COSV52945096; COSMIC: COSV52945096;