rs759858813

Variant names:

• chr19-11120482-C-G
• rs759858813
• NM_000527.5:c.2100C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11120482-C-G
• chr19-11120482-C-T

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.2100C>G (p.Asp700Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill SB criteria for FH from Malaysia (PMID:21418584), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585774/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: -2.54
• Publications: 11 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: 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.2100C>G	p.Asp700Glu	missense	Exon 14 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2100C>G	p.Asp700Glu	missense	Exon 14 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1977C>G	p.Asp659Glu	missense	Exon 13 of 17	NP_001182728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2100C>G	p.Asp700Glu	missense	Exon 14 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2358C>G	p.Asp786Glu	missense	Exon 14 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2100C>G	p.Asp700Glu	missense	Exon 14 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Hypercholesterolemia, familial, 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	0.079
DANN	Benign	0.96
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.6
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.9	L
PhyloP100		-2.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.093	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.73		Gain of solvent accessibility (P = 0.1376)
MVP		0.99
MPC		0.78
ClinPred		0.94	D
GERP RS		-11
Varity_R		0.46
gMVP		0.87
Mutation Taster		=1/99	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: rs759858813; hg19: chr19-11231158;