chr19-11102737-G-C

Variant names:

• chr19-11102737-G-C
• rs879254454
• NM_000527.5:c.264G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000527.5(LDLR):​c.264G>C​(p.Arg88Ser) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R88R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.125

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 5 ACMG points.

• PM1: In a disulfide_bond (size 20) in uniprot entity LDLR_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.264G>C	p.Arg88Ser	missense_variant	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.264G>C	p.Arg88Ser	missense_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.1	M;.;M;M;M
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.0	D;D;N;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0070	D;T;D;D;D
Sift4G	Benign	0.065	T;T;D;T;T
Polyphen		0.69	P;.;.;.;.
Vest4		0.45
MutPred		0.50		Loss of MoRF binding (P = 0.0612);Loss of MoRF binding (P = 0.0612);Loss of MoRF binding (P = 0.0612);Loss of MoRF binding (P = 0.0612);Loss of MoRF binding (P = 0.0612);
MVP		0.99
MPC		0.69
ClinPred		0.99	D
GERP RS		-0.50
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.92
gMVP		0.95

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: rs879254454; hg19: chr19-11213413;