rs879255139

chr19-11120481-A-G

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.2099A>G(p.Asp700Gly) variant causes a missense change. 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. D700E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 6.19

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 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr19-11120482-C-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 252221.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 19-11120481-A-G is Pathogenic according to our data. Variant chr19-11120481-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252220.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11120481-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2099A>G	p.Asp700Gly	missense_variant	14/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2099A>G	p.Asp700Gly	missense_variant	14/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	The NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4_Supporting, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - Level 1 assays: PMID 32015373: Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake. ---- activity is below 70% of wild-type, so PS3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with FH criteria (CT>95th percentile, plus tendon xanthomata or pCHD in proband or 1st degree and hypercholesterolemia in family) from Spain (PMID: 11668640) and at least 1 index case with SB criteria for FH from China (PMID: 22353362), so PS4_Supporting is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.875. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 700 of the LDLR protein (p.Asp700Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 33994402, 34456049). ClinVar contains an entry for this variant (Variation ID: 252220). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 32015373). This variant disrupts the p.Asp700 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15199436, 19118540, 23669246, 34869944). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.85
MutPred		0.81		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);
MVP		1.0
MPC		0.93
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.84
gMVP		0.95

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: rs879255139; hg19: chr19-11231157;