rs559239150

Positions:

• chr19-11123293-G-A
• chr19-11123293-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000527.5(LDLR):​c.2260G>A​(p.Gly754Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Benign (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.785

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1265341).
• BP6: Variant 19-11123293-G-A is Benign according to our data. Variant chr19-11123293-G-A is described in ClinVar as [Benign]. Clinvar id is 440687.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-11123293-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2260G>A	p.Gly754Arg	missense_variant	15/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2260G>A	p.Gly754Arg	missense_variant	15/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Benign, no assertion criteria provided

research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.36
DANN	Benign	0.58
DEOGEN2	Benign	0.36	T;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.43	T;T;T;T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L;.;.;.;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.010	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.63	T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T
Polyphen		0.0030	B;.;.;.;.;.
Vest4		0.18
MutPred		0.34		Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);.;.;.;Gain of sheet (P = 0.0073);
MVP		0.96
MPC		0.25
ClinPred		0.14	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.081
gMVP		0.69

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: rs559239150; hg19: chr19-11233969;