19-11111514-A-G

Position:

chr19-11111514-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1061A>G(p.Asp354Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D354A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

Splicing: ADA: 0.5468

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.21

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:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11111514-A-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 19-11111514-A-G is Pathogenic according to our data. Variant chr19-11111514-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11111514-A-G is described in Lovd as [Pathogenic]. Variant chr19-11111514-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1061A>G	p.Asp354Gly	missense_variant, splice_region_variant	8/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1061A>G	p.Asp354Gly	missense_variant, splice_region_variant	8/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251190

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135818

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461020

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726840

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:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 17, 2019	- -

Familial hypercholesterolemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 02, 2019	This missense variant (also known as p.Asp333Gly in the mature protein and as FH Munster-2) is located in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown a significantly reduced LDLR activity (15-30% of the wild type) in cells from a hypercholesterolemic individual compound heterozygous for this variant and a pathogenic p.Cys109Arg variant (also known as C88R) (PMID: 1301956). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 11810272, 19837725, 20145306, 29353225). This variant has been identified in 1/251190 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 28, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 354 of the LDLR protein (p.Asp354Gly). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp354 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 19837725). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251639). This variant is also known as D333G. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11810272, 19040724, 20145306, 29353225, 32770674; Invitae). This variant is present in population databases (rs755449669, gnomAD 0.003%). -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Sep 04, 2024	The p.Asp354Gly variant in LDLR has been reported in 4 individuals with familial hypercholesterolemia (PMID: 29353225, 1301956, 20145306, 11810272), and has been identified in 0.007% (6/91064) South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755449669). This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 251639). In vitro functional studies provide some evidence that the p.Asp354Gly variant may slightly impact protein function (PMID: 19040724). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Asp354Val and p.Asp354Ala, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 251640, 251638). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PP3_moderate, PM2_supporting, PM5_supporting, PS4_supporting, PS3_supporting (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 13, 2023	The LDLR c.1061A>G (p.Asp354Gly) variant has been reported in the published literature in several individuals affected with hypercholesterolemia (PMIDs: 32770674 (2020), 33740630 (2021), 33794673 (2021), 35741760 (2022)). A functional study reported a significant reduction in LDLR activity in cells carrying this variant with another pathogenic variant (PMID: 1301956 (1992)). The frequency of this variant in the general population, 0.000004 (1/251190 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a this variant significantly decreases LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as D333G and FH Munster-2; This variant is associated with the following publications: (PMID: 1301956, 32770674, 33740630, 33087929, 20145306, 35741760) -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2019

The p.Asp354Gly variant in LDLR (also described as p.Asp333Gly in the literature) has been reported in the compound heterozygous state in one individual with familial hypercholesterolemia (FH) who had a second pathogenic variant in LDLR (Hobbs 1992) and in the heterozygous state in at least 6 individuals with FH (Hobbs 1992, Fouchier 2001, Chmara 2010, Pek 2017, ClinVar: Variation ID 251639 ). In vitro functional studies provide some evidence that the p.Asp354Gly variant may impact protein function (Hobbs 1992). This variant has also been identified in 1/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs755449669). This frequency is low enough to be consistent with the frequency of FH in the general population. This variant is located in the first base of the exon, which is part of the 3’splice region. Computational prediction tools and conservation analysis suggest an impact both the protein and splicing. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp354Gly variant is likely pathogenic. The ACMG/AMP Criteria applied: PM2; PP3; PS3_Supporting; PS4_Moderate. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The p.D354G variant (also known as c.1061A>G), located in coding exon 8 of the LDLR gene, results from an A to G substitution at nucleotide position 1061. This variant impacts the first base pair of coding exon 8. The aspartic acid at codon 354 is replaced by glycine, an amino acid with similar properties, and is located in a cbEGF-like domain. This variant (also referred to as D333G and FH Munster-2) has been detected in individuals from familial hypercholesterolemia (FH) cohorts; however, in some cases, clinical details were limited and reported cases may overlap (Hobbs HH et al. Hum Mutat, 1992;1:445-66; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Chmara M et al. J Appl Genet, 2010;51:95-106; Pek SLT et al. Atherosclerosis, 2018 02;269:106-116; Saracoglu E et al. Echocardiography. 2018 09;35(9):1289-1299; Rieck L et al. Clin Genet, 2020 11;98:457-467; Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Turkyilmaz A et al. Metab Syndr Relat Disord. 2021 08;19(6):340-346). This variant was detected alone and with a second LDLR variant in individuals from FH cohorts who were reported to have reduced receptor activity in assays on patient cells (Mosig S et al. BMC Med Genomics, 2008 Nov;1:60; Hobbs HH et al. Hum Mutat, 1992;1:445-66). Based on internal structural analysis, this variant is predicted to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8; Mayhew M et al. Protein Eng. 1992 Sep;5(6):489-94; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;.;.;.;H

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.5

D;D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.96

MutPred

0.95

Loss of stability (P = 0.0811);Loss of stability (P = 0.0811);.;.;.;Loss of stability (P = 0.0811);

MVP

1.0

MPC

0.93

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.55

dbscSNV1_RF

Benign

0.66

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