rs759876319

chr19-11116141-G-A

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.1634G>A(p.Gly545Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G545R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.95

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 1 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 chr19-11116140-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 19-11116141-G-A is Pathogenic according to our data. Variant chr19-11116141-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116141-G-A is described in Lovd as [Pathogenic]. Variant chr19-11116141-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1634G>A	p.Gly545Glu	missense_variant	11/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1634G>A	p.Gly545Glu	missense_variant	11/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251474 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461612 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly545Glu variant in LDLR has been reported in 1 Pakistani family with familial hypercholesterolemia, segregated with disease in at least 8 affected relatives from 1 family (PMID: 23535506), and has been identified in 0.006533% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759876319). This variant has also been reported in ClinVar (VariationID: 251945) as pathogenic by Integrated Genetics and as likely pathogenic by the British Heart Foundation and Fulgent Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Gly545Trp, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 25741862, 29874871, 17765246;Variation ID: 251944). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_strong, PM5, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 545 of the LDLR protein (p.Gly545Glu). This variant is present in population databases (rs759876319, gnomAD 0.006%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 23535506). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251945). 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. This variant disrupts the p.Gly545 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26020417, 26343872; Invitae). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2016	Variant summary: The c.1634G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Glu. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 2/121362 control chromosomes at a frequency of 0.0000165, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0012508). This variant has been reported in 20 family members (3 homozygotes and 17 heterozygotes) in one large consanguineous family in Pakistan. Overall mean total cholesterol levels were significantly higher in carriers compared to non-carriers (6.9 mmol/l vs. 4.1 mmol/l p = 2.6E-07). The total cholesterol levels in homozygotes was significantly higher at an average of 11.4 mmol/L. In addition, p.G545R, p.G545W, p.G546R, p.G546D, p.G546V have been suggested to associate with FH, indicating Gly545, Gly546 are important for LDLR funcation. Taken together, this variant is classified as "Pathogenic" for Familial Hypercholesterolemia. -

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2019

The p.Gly545Glu variant in LDLR has been reported in 1 large Pakistani family with familial hypercholesterolemia (FH) and segregated with disease in 3 homozygous and 17 heterozygous affected relatives (Ahmed 2013). Overall mean total cholesterol levels were significantly higher in those family members with the p.Gly545Glu variant compared to those without. Additionally, total cholesterol levels in homozygotes was significantly higher than heterozygotes. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 251945) and has been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PP1_Strong, PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.5	L;.;.;.;.;L
MutationTaster	Benign	0.98	D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.60	P;.;.;.;.;.
Vest4		0.88
MutPred		0.84		Gain of ubiquitination at K544 (P = 0.0825);Gain of ubiquitination at K544 (P = 0.0825);.;.;.;Gain of ubiquitination at K544 (P = 0.0825);
MVP		1.0
MPC		0.93
ClinPred		0.87	D
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.97
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: rs759876319; hg19: chr19-11226817;