19-11105590-G-C

Position:

• chr19-11105590-G-C

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.684G>C​(p.Glu228Asp) 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E228K) has been classified as 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:3
• Conservation: PhyloP100: 0.626

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 ClinVar as 689346
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr19-11105588-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3691.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 19-11105590-G-C is Pathogenic according to our data. Variant chr19-11105590-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105590-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.684G>C	p.Glu228Asp	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.684G>C	p.Glu228Asp	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

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	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jul 18, 2018	The mutation at the protein level at position 228 leads to the amino acid substitution glutamic acid against aspartic acid (p.Glu228Asp, E228D). This change has not been described in the literature so far. However, prediction programs classify this mutation as pathogenic (Mutationtaster, SpliceSiteFinder). In addition, the mutation is located in a conserved region (Ser-Asp-Glu), which is essential for receptor function and in which many other pathogenic mutations have already been described. PMID: 20354512, 2988123, 28502510 -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu228 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2318961, 21475731, 21722902, 22390909, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects LDLR function (PMID: 31106925). 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. ClinVar contains an entry for this variant (Variation ID: 523724). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 28502510, 28964736, 31106925; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 228 of the LDLR protein (p.Glu228Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D;D;D
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.56	P;.;.;.
Vest4		0.67
MutPred		0.94		Loss of methylation at K225 (P = 0.1832);Loss of methylation at K225 (P = 0.1832);.;Loss of methylation at K225 (P = 0.1832);
MVP		1.0
MPC		0.56
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.91
gMVP		0.98

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: rs1208216597; hg19: chr19-11216266;