rs879254459

chr19-11102771-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.298G>A(p.Asp100Asn) 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. D100E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 8.06

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, 8 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 chr19-11102772-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251122.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11102771-G-A is Pathogenic according to our data. Variant chr19-11102771-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251121.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11102771-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.298G>A	p.Asp100Asn	missense_variant	3/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.298G>A	p.Asp100Asn	missense_variant	3/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP1, PP3, PP4, 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: This variant is absent from gnomAD (gnomAD v2.1.1) - PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID: 25936346. - PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID: 25936346 - PP3: REVEL = 0.93 - PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID: 25936346) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2021

The p.D100N variant (also known as c.298G>A and legacy p.D79N), located in coding exon 3 of the LDLR gene, results from a G to A substitution at nucleotide position 298. The aspartic acid at codon 100 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypercholesterolemia, including at least two homozygous cases (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Li H et al. Gene, 2015 Sep;569:313-7; Hu M et al. J. Atheroscler. Thromb., 2016 May;23:520-31; Moss S et al. Cardiovasc Revasc Med, 2018 12;19:20-22; Hsiung YC et al. Atherosclerosis, 2018 10;277:440-447). Based on internal structural analysis, this variant is deleterious, impacting a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 2 (Ambry internal data; Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2018

This sequence change replaces aspartic acid with asparagine at codon 100 of the LDLR protein (p.Asp100Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25936346). This variant is also known as D79N in the literature. ClinVar contains an entry for this variant (Variation ID: 251121). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.69
MutPred		0.93		Loss of phosphorylation at S99 (P = 0.2526);Loss of phosphorylation at S99 (P = 0.2526);Loss of phosphorylation at S99 (P = 0.2526);Loss of phosphorylation at S99 (P = 0.2526);Loss of phosphorylation at S99 (P = 0.2526);
MVP		1.0
MPC		0.79
ClinPred		1.0	D
GERP RS		4.6
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: rs879254459; hg19: chr19-11213447;