rs777640882

Positions:

• chr19-11102740-C-G
• chr19-11102740-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.267C>G​(p.Cys89Trp) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C89G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.826

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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11102738-T-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 19-11102740-C-G is Pathogenic according to our data. Variant chr19-11102740-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11102740-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.267C>G	p.Cys89Trp	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.267C>G	p.Cys89Trp	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2017

The p.C89W pathogenic mutation (also known as c.267C>G), located in coding exon 3 of the LDLR gene, results from a C to G substitution at nucleotide position 267. The cysteine at codon 89 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) and has been shown to segregrate with disease in two families (Heath KE et al. Atherosclerosis. 1999;143:41-54; Chaves FJ et al. J. Clin. Endocrinol. Metab. 2001;86:4926-32; Jelassi A et al. Atherosclerosis. 2009;203:449-53; Garcia-Garcia AB et al. Atherosclerosis. 2011;218:423-30). In addition, functional studies indicated that this variant causes a reduction in LDLR activity (Garcia-Garcia AB et al. Atherosclerosis. 2011;218:423-30). Three other alterations at the same codon (p.C89R, p.C89G, and p.C89Y) have also been associated with FH (Day IN et al. Hum Mutat. 1997;10(2):116-27; Bertolini S et al. Arterioscler Thromb Vasc Biol. 1999;19(2):408-18; Marduel M et al. Hum Mut. 2010;31(11):E1811-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.55	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;H
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-10	D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.78
MutPred		0.99		Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);
MVP		0.94
MPC		0.95
ClinPred		1.0	D
GERP RS		-3.3
Varity_R		1.0
gMVP		1.0

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: rs777640882; hg19: chr19-11213416;