rs879254678

chr19-11106667-A-Gchr19-11106667-A-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.797A>G(p.Asp266Gly) variant causes a missense change involving the alteration of a 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. D266E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.31

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 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 chr19-11106668-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 161287.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 19-11106667-A-G is Pathogenic according to our data. Variant chr19-11106667-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251457.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11106667-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.797A>G	p.Asp266Gly	missense_variant	5/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.797A>G	p.Asp266Gly	missense_variant	5/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Nov 14, 2021	The NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.796A>T (p.Asp266Tyr) (ClinVar ID 251456) – Pathogenic by these guidelines, - NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 3 variants in the same codon classified as Pathogenic by these guidelines; PM2 - This variant is absent from gnomAD (gnomAD v2.1.1); PP3 - REVEL = 0.98; PP4 - Identified in 2 unrelated index cases fulfilling Simon-Broome criteria (published in PMID: 32331935); PS4_Supporting - Variant meets PM2. Identified in 2 unrelated index cases fulfilling Simon-Broome criteria (published in PMID: 32331935); -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2022

The p.D266G variant (also known as c.797A>G), located in coding exon 5 of the LDLR gene, results from an A to G substitution at nucleotide position 797. The aspartic acid at codon 266 is replaced by glycine, an amino acid with similar properties. This alteration, which is also known as p.D245G, has been reported in individuals with familial hypercholesterolemia (FH) (Hobbs HH et al. Hum Mutat, 1992;1:445-66; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Tada H et al. Pract Lab Med, 2015 Apr;1:22-27). This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 6 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). Based on internal structural analysis, this alteration has a deleterious impact. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2022

This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 12417285, 15256764, 28932795, 32331935). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11196104, 20663204, 21310417, 22698793, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 251457). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 266 of the LDLR protein (p.Asp266Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.6	H;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.85
MutPred		0.94		Gain of catalytic residue at D266 (P = 0.0366);Gain of catalytic residue at D266 (P = 0.0366);.;.;Gain of catalytic residue at D266 (P = 0.0366);
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs879254678; hg19: chr19-11217343;