chr19-11123322-G-T

Position:

chr19-11123322-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000527.5(LDLR):c.2289G>T(p.Glu763Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,096 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 5 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: 0.735

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01747179).

BP6

Variant 19-11123322-G-T is Benign according to our data. Variant chr19-11123322-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 226389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11123322-G-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2289G>T	p.Glu763Asp	missense_variant	15/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2289G>T	p.Glu763Asp	missense_variant	15/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251144

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135816

show subpopulations

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:

0.00216

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000133

AC:

195

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727220

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:

0.00217

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 13, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	literature only;research	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 31, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2018	See Variant Classification Assertion Criteria. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2017

The p.Glu763Asp variant in LDLR has been reported in 2 individuals with hypercholesterolemia (Hooper 2012, Bangash 2014). This variant has been identified in 0.21% (66/30782) of South Asian chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs774698247) and is reported in ClinVar (Variation ID: 226389). Computational prediction tools and conservation analysis suggest that the p.Glu763Asp variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the p.Glu763Asp variant is likely benign due to its frequency in the general population. ACMG/AMP Criteria applied: PS4_Supporting, BP4, BS1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;.;.;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.71

T;T;T;T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.017

T;T;T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.4

M;.;.;.;.;M

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.99

N;N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.32

T;T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T;T

Polyphen

0.74

P;.;.;.;.;.

Vest4

0.14

MutPred

0.45

Loss of catalytic residue at E763 (P = 0.046);Loss of catalytic residue at E763 (P = 0.046);.;.;.;Loss of catalytic residue at E763 (P = 0.046);

MVP

1.0

MPC

0.20

ClinPred

0.043

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.083

gMVP

0.75

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