rs374045590

Variant names:

• chr19-11129598-C-A
• rs374045590
• NM_000527.5:c.2475C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11129598-C-A
• chr19-11129598-C-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PS4 PP1_Strong PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong) 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= 0.00001 in European (Non-Finnish) population (gnomAD v2.1.1).PP3: REVEL = 0.802.PS3: Level 1 experiment using heterologous cells (CHO), the experiments shown 50-60% LDL uptake, and normal LDL-LDLR binding (95%) and normal cell surface LDLR (95%), Etxebarria et al, 2015, Unidad de Biofísica (CSIC, UPV/EHU), Departamento de Bioquímica, Universidad del País Vasco, Spain, PMID25378237.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4: Variant meets PM2 and is identified in 22 unrelated index cases who fulfil FH diagnostic criteria. Four index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), three of them had DLCN score ≥6, one met Simon Broome possible for FH. Three index cases with DLCN score ≥6, from Robarts Research Institute, Canada. One case fulfil criteria of TC and LDLc higher than the 95th percentile, with presence of tendon xanthomata, CAD in the proband or in a first degree relative, Chaves et al, 2001, Institute of cytological research and service of endocrinology and nutrition, University of Valencia, Spain, PMID 11600564. Fourteen index cases fulfil 2 of 3 criteria of: 1) TC>8mmol/l, LDL>6mmol/l, TG<2.5mmol/l, 2) CAD before 60yr or family history of CAD, 3) presence of tendon xanthoma, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394.PP1_Strong: Variant segregates with FH phenotype in 16 informative meiosis from more than 3 families. Two affected relatives, one each from 2 families tested positive for the variant from Robarts Research Institute, Canada. Fourteen affected relatives from unknown number of families tested positive for the variant, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394.PS1 not met: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic by these guidelines, therefore PS1 is not met. PM5 not met: One other missense variants in the same codon: NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp), (ClinVarID 252340) is classified as Likely Pathogenic by these guidelines, therefore PM5 not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA040801/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: -0.0920
• Publications: 12 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2475C>A	p.Asn825Lys	missense	Exon 17 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2475C>A	p.Asn825Lys	missense	Exon 17 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2352C>A	p.Asn784Lys	missense	Exon 16 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.2475C>A	p.Asn825Lys	missense	Exon 17 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2733C>A	p.Asn911Lys	missense	Exon 17 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2475C>A	p.Asn825Lys	missense	Exon 17 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

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: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111960

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

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000726 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Hypercholesterolemia, familial, 1 (5)
3	-	-	Familial hypercholesterolemia (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-0.092
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.93		Gain of ubiquitination at N825 (P = 0.0138)
MVP		1.0
MPC		0.87
ClinPred		0.99	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
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: rs374045590; hg19: chr19-11240274;