rs372845091

Positions:

• chr19-11102764-C-G
• chr19-11102764-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.291C>G​(p.Asn97Lys) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N97N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.90

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 2) in uniprot entity LDLR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 19-11102764-C-G is Pathogenic according to our data. Variant chr19-11102764-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11102764-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.291C>G	p.Asn97Lys	missense_variant	3/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.291C>G	p.Asn97Lys	missense_variant	3/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, 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	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	0.22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D;.;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.1	M;.;M;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.75
MutPred		0.70		Gain of ubiquitination at N97 (P = 0.006);Gain of ubiquitination at N97 (P = 0.006);Gain of ubiquitination at N97 (P = 0.006);Gain of ubiquitination at N97 (P = 0.006);Gain of ubiquitination at N97 (P = 0.006);
MVP		1.0
MPC		0.85
ClinPred		1.0	D
GERP RS		-9.3
Varity_R		0.69
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372845091; hg19: chr19-11213440;