chr19-11105587-C-A

Position:

• chr19-11105587-C-A

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.681C>A​(p.Asp227Glu) 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.218

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 22 ACMG points.

• PS1: Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 2) in uniprot entity LDLR_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) 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 chr19-11105586-A-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-11105587-C-A is Pathogenic according to our data. Variant chr19-11105587-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 403632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105587-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.681C>A	p.Asp227Glu	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.681C>A	p.Asp227Glu	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt SDE motif. SDE bind structural Ca2+. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2022	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2022

Also known as p.D206E and FH-Afrikans; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11491306, 7682459, 27680772, 29128982, 28502495, 18718593, 31491741, 32331935, 17087781) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2021

The p.D227E pathogenic mutation (also known as c.681C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration, which is also known as p.D206E, has been reported in familial hypercholesterolemia (FH) cohorts in both the heterozygous and homozygous states (Charng MJ et al. Eur J Clin Invest, 2006 Dec;36:866-74; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Hori M et al. Atherosclerosis, 2019 10;289:101-108). In addition, a different alteration located at the same position, resulting in the same protein change, c.681C>G (p.D227E), is a founder mutation that accounts for the majority of FH in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82) and had also been reported in affected individuals of multiple ethnicities (Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17087781, 17539906, 19467224, 21310417, 21382890, 22883975, 31491741). This variant is also known as Asp206Glu. ClinVar contains an entry for this variant (Variation ID: 403632). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Benign	0.032
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.74
MutPred		0.95		Loss of ubiquitination at K225 (P = 0.0853);Loss of ubiquitination at K225 (P = 0.0853);.;Loss of ubiquitination at K225 (P = 0.0853);
MVP		1.0
MPC		0.78
ClinPred		0.99	D
GERP RS		-0.20
Varity_R		0.96
gMVP		0.99

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: rs121908028; hg19: chr19-11216263;