rs121908030

chr19-11107484-G-Achr19-11107484-G-Cchr19-11107484-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.910G>A(p.Asp304Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,596 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D304E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 9.81

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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 chr19-11107486-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226336.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 19-11107484-G-A is Pathogenic according to our data. Variant chr19-11107484-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3692.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11107484-G-A is described in Lovd as [Pathogenic]. Variant chr19-11107484-G-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.910G>A	p.Asp304Asn	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.910G>A	p.Asp304Asn	missense_variant	6/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

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:

251318

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457672

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725092

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
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, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 10, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Dec 17, 2021	The NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3_moderate, PS4, PP1_strong, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.883. It is above 0.75, so PP3 is Met. PS3_moderate - 2 Level 2 assays performed by different labs: PMID 2088165: Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity. PMID 6438436: Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity. 2 Level 3 assays performed by different labs: PMID 4061492: Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activity PMID 6438436: Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity ---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met. PS4 - Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID: 21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID: 23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID: 12436241), so PS4 is Met. PP1_strong - Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met. PM3 - Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met. PP4 - Variant meets PM2 and is identified in at least 14 unrelated index cases as described in PS4, PP4 is Met. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 10, 2018	This c.910G>A (p.Asp304Asn) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9664576, 11810272, 12436241, 21418584, 21310417) and is extremely rare in the general population. Functional studies have shown that the mutant LDLR protein retains only 5-15% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). This c.910G>A (p.Asp304Asn) variant in the LDLR gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	This missense variant (also known as p.Asp283Asn in the mature protein and as FH Denver-2) replaces aspartic acid with asparagine at codon 304 in the LDLR type A repeat 7 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies using fibroblasts from patients with homozygous familial hypercholesterolemia have shown that this variant causes a significant reduction in LDLR activity (PMID: 1301956, 6438436). Another in-vitro functional study has shown that this variant causes in increase in LDLR retention in the endoplasmic reticulum (PMID: 11939787). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 4061491, 9664576, 11810272, 17094996, 21418584, 23064986, 34037665). This variant has also been observed in compound heterozygous state in multiple individuals affected with homozygous familial hypercholesterolemia (PMID: 4061491, 17094996, 27678436, 31048103), indicating that this variant contributes to disease. This variant has been identified in 3/282666 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asp304Glu and p.Asp304Tyr, are considered to be disease-causing (ClinVar variation ID: 226336 and 251517), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1988	- -

Familial hypercholesterolemia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 304 of the LDLR protein (p.Asp304Asn). This variant is present in population databases (rs121908030, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2088165, 9664576, 11810272, 12436241, 21418584, 22698793). This variant is also known as Denver-2 and D283N. ClinVar contains an entry for this variant (Variation ID: 3692). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956). This variant disrupts the p.Asp304 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 17094996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2020	Variant summary: LDLR c.910G>A (p.Asp304Asn) results in a conservative amino acid change located in the LDL-receptor class A7 domain (Guo_2019) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes (gnomAD and publication data). c.910G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Hobbs_1990, Al-Khateeb_2011, Luirink_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and variant effect results in 5-15 % of normal activity (Hobbs_1992). Additionally, other variants at this codon (p.D304E/H/Y/V) have been reported in individuals with Familial Hypercholesterolemia and are considered as likely pathogenic/pathogenic (HGMD database). This suggests that the asparagine at codon 304 of the LDLR protein is critical for protein function. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (5x) and likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2023	This missense variant (also known as p.Asp283Asn in the mature protein and as FH Denver-2) replaces aspartic acid with asparagine at codon 304 in the LDLR type A repeat 7 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies using fibroblasts from patients with homozygous familial hypercholesterolemia have shown that this variant causes a significant reduction in LDLR activity (PMID: 1301956, 6438436). Another in-vitro functional study has shown that this variant causes in increase in LDLR retention in the endoplasmic reticulum (PMID: 11939787). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 4061491, 9664576, 11810272, 17094996, 21418584, 23064986, 34037665). This variant has also been observed in compound heterozygous state in multiple individuals affected with homozygous familial hypercholesterolemia (PMID: 4061491, 17094996, 27678436, 31048103), indicating that this variant contributes to disease. This variant has been identified in 3/282666 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asp304Glu and p.Asp304Tyr, are considered to be disease-causing (ClinVar variation ID: 226336 and 251517), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate significantly reduced LDL receptor activity compared to wild type (Hobbs et al., 1990; Hobbs et al., 1992); Also known as FH Denver-2 and p.D283N; This variant is associated with the following publications: (PMID: 2318961, 12436241, 31447099, 25637381, 25487149, 24507775, 2088165, 9664576, 11810272, 17094996, 21418584, 22698793, 34037665, 30795984, 1301956, 33740630, 32719484) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 05, 2019	The frequency of this variant in the general population, 0.00012 (3/24946 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant was identified in multiple individuals affected with hypercholesterolemia (PMID: 11810272 (2001), 12436241 (2002), 21418584 (2011), 22698793 (2012), 23064986 (2012), 24507775 (2014), 33740630 (2021), 34037665 (2021)). The variant has also been reported as compound heterozygous with another pathogenic variant in children with a severe presentation (PMID: 27678436 (2016), 30795984 (2019)). Functional studies of homozygous cultured fibroblasts showed a retention of only 5-15% LDLR activity (PMID: 1301956 (1992)). Based on the available information, this variant is classified as pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 06, 2018

The p.Asp304Asn variant in LDLR (also described as p.Asp283Asn in the literature ) has been reported in at least 14 individuals (in at least 1 in the homozygous state and at least 13 in the heterozygous state) with familial hypercholesterol emia (FH; Hobbs 1990, Callis 1998, Fouchier 2001, Ansellem 2002, Al-Khateeb 2011 , Tichy 2012, Do 2015). In vitro functional studies provide some evidence that t he p.Asp304Asn variant may impact protein function (Hobbs 1990). This variant ha s also been reported by other clinical laboratories in ClinVar (Variation ID: 36 92) and has been identified in 3/24012 African chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908030). Thi s frequency is consistent with the frequency of FH in the general population. Co mputational prediction tools and conservation analysis suggest that the p.Asp304 Asn variant may impact the protein. In addition, four other variants at this pos ition have been reported in individuals with FH (HGMD database, Stenson 2017), w ith at least one classified as likely pathogenic or pathogenic, suggesting that changes at this position are not tolerated. In summary, this variant meets crit eria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, low frequency in the general po pulation, the presence of a different pathogenic variant at the same codon, and functional and computational evidence. ACMG/AMP Criteria applied (Richards 2015) : PS4; PM2; PM5; PP3; PS3_Supporting. -

Hypercholesterolemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The p.D304N pathogenic mutation (also known as c.910G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 910. The aspartic acid at codon 304 is replaced by asparagine, an amino acid with highly similar properties. This mutation (also referred to as p.D283N and Denver-2) has been reported in numerous familial hypercholesterolemia (FH) cohorts (Callis M et al. Mol. Cell. Probes. 1998;12:149-52; Fouchier SW et al. Hum. Genet. 2001;109:602-15; Amsellem S et al. Hum. Genet. 2002;111:501-10; Tosi I et al. Atherosclerosis. 2007;194:102-11; Al-Khateeb A et al. BMC Med. Genet. 2011;12:40; Ahmad Z et al. Circ Cardiovasc Genet. 2012;5:666-75). It has also been described in the homozygous state in an individual whose LDL receptor activity was 5-15% of normal activity and in the compound heterozygous state with the likely pathogenic alteration LDLR p.E101K in an individual with homozygous FH (Bilheimer DW et al. Am. J. Med. Genet. 1985;22:593-8; Khoo KL et al. J Clin Lipidol. 2016;10:1188-94). Functional studies suggest this mutation results in defective transport of the LDLR protein (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Li Y et al. Biochemistry. 2002;41:4921-8). In addition, three other alterations affecting the same codon (p.D304V, p.D304E, and p.D304Y) have been associated with FH (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Loux N et al. Hum. Mutat. 1992;1:325-32; Lombardi MP et al. Genet. Test. 2006;10:77-84). 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

0.76

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;.;.;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

D;D;D;D;D;D

Sift

Benign

0.060

T;T;T;T;D;D

Sift4G

Benign

0.061

T;T;T;T;T;T

Polyphen

0.87

P;.;.;.;.;.

Vest4

0.89

MVP

1.0

MPC

0.79

ClinPred

0.99

GERP RS

5.3

Varity_R

0.68

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