rs1057519651

Positions:

• chr19-11089601-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000527.5(LDLR):​c.53C>T​(p.Ala18Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.853

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-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15198213).
• BP6: Variant 19-11089601-C-T is Benign according to our data. Variant chr19-11089601-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 375773.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.53C>T	p.Ala18Val	missense_variant	1/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.53C>T	p.Ala18Val	missense_variant	1/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 16, 2016

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	9.7
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T;.;.;.;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.4	L;.;L;L;L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.53	T;T;D;T;D;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.013	B;.;.;.;.;.
Vest4		0.25
MutPred		0.42		Gain of MoRF binding (P = 0.1267);Gain of MoRF binding (P = 0.1267);Gain of MoRF binding (P = 0.1267);Gain of MoRF binding (P = 0.1267);Gain of MoRF binding (P = 0.1267);Gain of MoRF binding (P = 0.1267);
MVP		1.0
MPC		0.22
ClinPred		0.099	T
GERP RS		2.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Varity_R		0.057
gMVP		0.70

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: rs1057519651; hg19: chr19-11200277;