rs767618089

chr19-11107472-A-Gchr19-11107472-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):c.898A>G(p.Arg300Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,300 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. R300K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:2
• Conservation: PhyloP100: -0.651

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 14 ACMG points.

• PM1: In a hotspot region, there are 12 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 19-11107472-A-G is Pathogenic according to our data. Variant chr19-11107472-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251510.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.898A>G	p.Arg300Gly	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.898A>G	p.Arg300Gly	missense_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251386 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458300 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725458

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25545329). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR -related disorder (ClinVar ID: VCV000251510 / PMID: 19318025). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25545329 , 28965616 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 21, 2022	PS3, PS4_Moderate, PM1, PM2 -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant (also known as p.Arg279Gly in the mature protein) replaces arginine with glycine at codon 300 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies in LDLR-deficient cells indicated that this variant resulted in normal LDLR expression, but caused partial impairment (~50-60%) in LDL binding and uptake compared to wild-type LDLR (PMID: 25545329). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 19446849, 23375686, 27578128, 27784735, 28965616, 30293936, 32757650; ClinVar SCV002572850.1; SCV000583755.1). This variant has been identified in 3/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, 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	Oct 28, 2022	The NM_000527.5(LDLR):c.898A>G (p.Arg300Gly) variant is classified as likely Pathogenic variant for Familial Hypercholesterolemia by applying evidence code PM2, PS3 and PS4 supporting 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: PM2_Met : PopMax MAF = 0.00003 in European (Non-Finnish) exomes (gnomAD v2.1.1) PS3_Met : Level 1 assay: Study of the whole LDLR cycle in Heterologous cells (CHO-ldlA7 cells), WB+FACS+CLSM. LDLR expression was not statistically different as compared to control. Conversely, LDL binding (<60%) and uptake (<60%) were significantly decreased (P<0.001). Interestingly, although the variant affects LDL binding and uptake, do not affect VLDL uptake. This reveals that the conformational change occurring in the module does not propagate to the whole ligand binding domain. (from PMID:25545329) -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

LDLR: PM1, PM2, PS4:Moderate, PS3:Supporting -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The p.R300G variant (also known as c.898A>G), located in coding exon 6 of the LDLR gene, results from an A to G substitution at nucleotide position 898. The arginine at codon 300 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Additionally, an in vitro assay showed this alteration may reduce protein function (Etxebarria A et al. Atherosclerosis, 2015 Feb;238:304-12). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	13
Dann	Benign	0.93
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.83	T;T;T;T;D;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.0	M;.;.;.;.;M
MutationTaster	Benign	0.86	D;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D
Sift	Uncertain	0.019	D;D;D;D;D;D
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.84	P;.;.;.;.;.
Vest4		0.69
MutPred		0.60		Gain of catalytic residue at N297 (P = 0.0743);Gain of catalytic residue at N297 (P = 0.0743);.;.;.;Gain of catalytic residue at N297 (P = 0.0743);
MVP		1.0
MPC		0.85
ClinPred		0.83	D
GERP RS		-4.4
Varity_R		0.87
gMVP		0.92

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: rs767618089; hg19: chr19-11218148;