19-11105457-G-C

Position:

• chr19-11105457-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3 PP4 PM1

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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.551G>C	p.Cys184Ser	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.551G>C	p.Cys184Ser	missense_variant	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 22, 2016

Variant summary: The LDLR c.551G>C (p.Cys184Ser) variant involves the alteration of a conserved nucleotide. This variant is located in the Low-density lipoprotein (LDL) receptor class A repeat domain (InterPro). Although the substitution does not exhibit a shift in polarity, 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121044 control chromosomes. One database lists this variant in an individual without clinical information. Other variants affecting the same amino acids, p.Cys184Arg, p.Cys184Tyr, p.Cys184Trp, have been clssified as pathogenic/likely pathogenic in ClinVar. Taken together, this variant is classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.5	M;.;.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.7	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.86		Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);.;Gain of disorder (P = 0.0128);
MVP		1.0
MPC		0.90
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.97
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908039; hg19: chr19-11216133;