rs879255092

Variant names:

• chr19-11120219-T-C
• rs879255092
• NM_000527.5:c.1973T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.1973T>C​(p.Leu658Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L658L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.99
• 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: 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 22 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 19-11120219-T-C is Pathogenic according to our data. Variant chr19-11120219-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 252138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1973T>C	p.Leu658Pro	missense	Exon 13 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1973T>C	p.Leu658Pro	missense	Exon 13 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1850T>C	p.Leu617Pro	missense	Exon 12 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1973T>C	p.Leu658Pro	missense	Exon 13 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2231T>C	p.Leu744Pro	missense	Exon 13 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1973T>C	p.Leu658Pro	missense	Exon 13 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000426 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1, family member=1/Software predictions: Conflicting

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.026
Eigen_PC	Benign	-0.034
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.0
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.77	P
Vest4		0.76
MutPred		0.67		Gain of sheet (P = 0.0085)
MVP		1.0
MPC		0.89
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.90
gMVP		0.98
Mutation Taster		=14/86	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: rs879255092; hg19: chr19-11230895;