chr19-11105439-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000527.5(LDLR):c.533A>T(p.Asp178Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,738 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. D178E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.20

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 31 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr19-11105440-T-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 251287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 19-11105439-A-T is Pathogenic according to our data. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11105439-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 226326.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.533A>T	p.Asp178Val	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.533A>T	p.Asp178Val	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2

Sep 30, 2011

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

1.0

D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.7

H;.;.;H

PhyloP100

9.2

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-8.2

D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.95

MutPred

0.87

Loss of disorder (P = 0.0173);Loss of disorder (P = 0.0173);.;Loss of disorder (P = 0.0173);

MVP

1.0

MPC

0.98

ClinPred

1.0

GERP RS

5.6

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over