rs879255182

Variant names:

• chr19-11128056-T-A
• rs879255182
• NM_000527.5:c.2360T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM2 PP2 PP3_Strong BP6

The NM_000527.5(LDLR):​c.2360T>A​(p.Val787Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V787M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0240
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• 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, 0.959
• BP6: Variant 19-11128056-T-A is Benign according to our data. Variant chr19-11128056-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252292.

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.2360T>A	p.Val787Glu	missense	Exon 16 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2360T>A	p.Val787Glu	missense	Exon 16 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.2237T>A	p.Val746Glu	missense	Exon 15 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.2360T>A	p.Val787Glu	missense	Exon 16 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2618T>A	p.Val873Glu	missense	Exon 16 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2360T>A	p.Val787Glu	missense	Exon 16 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:1

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	7.9
DANN	Benign	0.92
DEOGEN2	Uncertain	0.80	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.024
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		0.41	B
Vest4		0.60
MutPred		0.85		Gain of disorder (P = 0.0032)
MVP		1.0
MPC		0.42
ClinPred		0.31	T
GERP RS		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.30
gMVP		0.95
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs879255182; hg19: chr19-11238732; COSMIC: COSV52942448; COSMIC: COSV52942448;