19-11106667-A-G

Variant names:

• chr19-11106667-A-G
• rs879254678
• NM_000527.5:c.797A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PS4_Supporting PP3 PP4 PM5_Strong

This summary comes from the ClinGen Evidence Repository: 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); LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585136/MONDO:0007750/013

• 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 Likely_pathogenic. Variant got 9 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.797A>G	p.Asp266Gly	missense_variant	Exon 5 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.797A>G	p.Asp266Gly	missense_variant	Exon 5 of 18	1	NM_000527.5	ENSP00000454071.1

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

Nov 14, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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); -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Apr 11, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 12417285, 15256764, 28932795, 32331935). 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
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D
REVEL	Pathogenic	0.97
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;