19-11113287-C-A

Position:

chr19-11113287-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 5.89

Variant links:

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]

LDLR links:

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ACMG classification

Classification made for transcript

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: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=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 linkuse as main transcript	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 linkuse as main transcript	c.1196C>A	p.Ala399Asp	missense_variant	9/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460742

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726696

show subpopulations

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

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

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). -
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). -

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

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;.;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.0

L;.;.;.;.;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.6

D;D;N;D;N;D

REVEL

Pathogenic

0.82

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over