NM_000527.5:c.81C>G

Variant names:

• chr19-11100236-C-G
• rs2228671
• NM_000527.5:c.81C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS4 PM1 PM2 PP3 PP4 PP1 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, 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:PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed.PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1).PS3_moderate: PMID:1301956 - Level 2 assay- study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%.PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible- 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6- 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6- 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6-as well as >10 cases from (PMID:1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology)PP3: REVEL = 0.759PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA041664/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:33 B:1
• Conservation: PhyloP100: -0.152
• Publications: 159 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 13 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.81C>G	p.Cys27Trp	missense	Exon 2 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.81C>G	p.Cys27Trp	missense	Exon 2 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.81C>G	p.Cys27Trp	missense	Exon 2 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.81C>G	p.Cys27Trp	missense	Exon 2 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.339C>G	p.Cys113Trp	missense	Exon 2 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.81C>G	p.Cys27Trp	missense	Exon 2 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250746 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460888 Hom.: 1 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 726738

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52500

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74178

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00000150 Hom.: 4114

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
22	-	1	Hypercholesterolemia, familial, 1 (23)
5	-	-	Familial hypercholesterolemia (5)
4	-	-	not provided (4)
1	-	-	Cardiovascular phenotype (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		-0.15
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.83		Loss of loop (P = 0.1242)
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		-1.7
Varity_R		0.98
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: rs2228671; hg19: chr19-11210912;