rs879255137

Positions:

• chr19-11120476-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000527.5(LDLR):​c.2094C>G​(p.Cys698Trp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C698F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.513

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain EGF-like 3 (size 49) in uniprot entity LDLR_HUMAN there are 49 pathogenic changes around while only 4 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 chr19-11120475-G-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11120476-C-G is Pathogenic according to our data. Variant chr19-11120476-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252217.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2094C>G	p.Cys698Trp	missense_variant	14/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2094C>G	p.Cys698Trp	missense_variant	14/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

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 prediction damaging -
Uncertain significance, 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

Sep 20, 2019

The p.C698W variant (also known as c.2094C>G), located in coding exon 14 of the LDLR gene, results from a C to G substitution at nucleotide position 2094. The cysteine at codon 698 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been reported in individuals with familial hypercholesterolemia, including one compound heterozygote case with severe hypercholesterolemia and tendon xanthoma (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 3 domain (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Alternate amino acid substitutions at this position (legacy p.C677), p.C698Y, p.C698F, p.C698R, have also been reported in FH cohorts (Salazar LA et al. Hum. Mutat., 2002 Apr;19:462-3; Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14; Pein I et al. Ann. Hum. Genet., 2013 Jan;77:22-30). 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	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.5	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.71	P;.;.;.;.
Vest4		0.97
MutPred		0.93		Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);.;.;Loss of disorder (P = 0.0663);
MVP		1.0
MPC		0.69
ClinPred		1.0	D
GERP RS		-0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.99
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: rs879255137; hg19: chr19-11231152;