rs879254810

Variant names:

• chr19-11111611-C-G
• rs879254810
• NM_000527.5:c.1158C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11111611-C-G
• chr19-11111611-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1158C>G (p.Asp386Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, 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: This variant is absent in gnomAD (gnomAD v2.1.1).PP4: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585332/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:1
• Conservation: PhyloP100: 0.709
• Publications: 3 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: Uncertain_significance. The variant received 3 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.

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.1158C>G	p.Asp386Glu	missense	Exon 8 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1158C>G	p.Asp386Glu	missense	Exon 8 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1035C>G	p.Asp345Glu	missense	Exon 7 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.1158C>G	p.Asp386Glu	missense	Exon 8 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1416C>G	p.Asp472Glu	missense	Exon 8 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1158C>G	p.Asp386Glu	missense	Exon 8 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461376 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726982

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.71
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.042	D
Polyphen		0.047	B
Vest4		0.37
MutPred		0.55		Gain of methylation at K390 (P = 0.0953)
MVP		1.0
MPC		0.25
ClinPred		0.96	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.96
Mutation Taster		=1/99	disease causing

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: rs879254810; hg19: chr19-11222287;