rs875989918

chr19-11113287-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000527.5(LDLR):c.1196C>A(p.Ala399Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,742 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A399S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.89

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 11 ACMG points.

• PM1: In a hotspot region, there are 10 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 chr19-11113286-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 440632.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-11113287-C-A is Pathogenic according to our data. Variant chr19-11113287-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226350.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr19-11113287-C-A is described in Lovd as [Pathogenic]. Variant chr19-11113287-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1196C>A	p.Ala399Asp	missense_variant	9/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1196C>A	p.Ala399Asp	missense_variant	9/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460742 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726696

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Mar 26, 2010	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ala399Asp variant in LDLR has been reported in 3 individuals with familial hypercholesterolemia (PMID: 22883975, 9259195, 11810272), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 226350). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala399 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10634824, 15241806, 16250003, 16343504, 21925044, 23375686, 26723464). 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: 226350). This variant is also known as A378D. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 11810272, 21382890, 22883975; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 399 of the LDLR protein (p.Ala399Asp). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2018

The p.A399D pathogenic mutation (also known as c.1196C>A), located in coding exon 9 of the LDLR gene, results from a C to A substitution at nucleotide position 1196. The alanine at codon 399 is replaced by aspartic acid, an amino acid with dissimilar properties, and is located in the EGF precursor-like domain. This variant (also described as p.A378D) has been reported in multiple individuals from a variety of ethnic backgrounds with familial hypercholesterolemia (FH) (Day IN et al. Hum. Mutat., 1997;10:116-27; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). In addition, an alternate amino acid substitution at this position, p.A399T (also known as p.A378T or FH-Nuoro), has also been reported in individuals with FH (Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.0	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;D;N;D;N;D
Sift	Uncertain	0.0030	D;T;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.94	P;.;.;.;.;.
Vest4		0.78
MutPred		0.94		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;.;.;Gain of relative solvent accessibility (P = 0.09);
MVP		1.0
MPC		0.87
ClinPred		0.95	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.98

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: rs875989918; hg19: chr19-11223963;