19-11105457-G-C

Variant names:

• chr19-11105457-G-C
• rs121908039
• NM_000527.5:c.551G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.551G>C (p.Cys184Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, 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 Cys184, one of the cysteine residues listed.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.871. It is above 0.75.PP4 - Variant meets PM2 and is identified in 1 index case who fulfills DLCN>=6 criteria for FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France, after alternative causes for high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404077216/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 9.72
• Publications: 26 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.551G>C	p.Cys184Ser	missense	Exon 4 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.551G>C	p.Cys184Ser	missense	Exon 4 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.428G>C	p.Cys143Ser	missense	Exon 3 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.551G>C	p.Cys184Ser	missense	Exon 4 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.809G>C	p.Cys270Ser	missense	Exon 4 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.551G>C	p.Cys184Ser	missense	Exon 4 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.86		Gain of disorder (P = 0.0128)
MVP		1.0
MPC		0.90
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.97
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: rs121908039; hg19: chr19-11216133;