rs1135402781

chr19-11123217-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000527.5(LDLR):c.2184G>C(p.Arg728Ser) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.217

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1376496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2184G>C	p.Arg728Ser	missense_variant	15/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2184G>C	p.Arg728Ser	missense_variant	15/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Mar 01, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	5.0
Dann	Benign	0.86
DEOGEN2	Benign	0.36	T;.;.;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N
Sift	Benign	0.42	T;T;T;T;T;T
Sift4G	Benign	0.81	T;T;T;T;T;T
Polyphen		0.083	B;.;.;.;.;.
Vest4		0.16
MutPred		0.36		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;.;.;Loss of sheet (P = 0.0126);
MVP		0.98
MPC		0.24
ClinPred		0.091	T
GERP RS		-0.61
Varity_R		0.18
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1135402781; hg19: chr19-11233893;