19-11128060-G-T

Variant names:

• chr19-11128060-G-T
• rs879255183
• NM_000527.5:c.2364G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PP2 PP3_Moderate BP6

The NM_000527.5(LDLR):​c.2364G>T​(p.Arg788Ser) 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 benign outcome for this variant. 15/24 in silico tools predict a benign 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. R788K) 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: -0.525
• 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: Uncertain_significance. The variant received 4 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-11128060-G-T is Benign according to our data. Variant chr19-11128060-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252293.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2364G>T	p.Arg788Ser	missense_variant	Exon 16 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2364G>T	p.Arg788Ser	missense_variant	Exon 16 of 18	1	NM_000527.5	ENSP00000454071.1

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

Familial hypercholesterolemia Uncertain:1

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 788 of the LDLR protein (p.Arg788Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 23375686). ClinVar contains an entry for this variant (Variation ID: 252293). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hypercholesterolemia, familial, 1 Benign:1

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.69
DEOGEN2	Benign	0.31	T;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.25	T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.092	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.34	N;.;.;.;.;N
PhyloP100		-0.53
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.5	N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.92	T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.14
MutPred		0.59		Gain of disorder (P = 0.0368);Gain of disorder (P = 0.0368);.;.;.;Gain of disorder (P = 0.0368);
MVP		0.96
MPC		0.24
ClinPred		0.043	T
GERP RS		-0.081
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.082
gMVP		0.85
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255183; hg19: chr19-11238736;