NM_000527.5:c.910G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS3_ModeratePS4PP1_StrongPM3PM2PP3PP4

This summary comes from the ClinGen Evidence Repository: 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 activityPMID 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023792/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

11
5
3

Clinical Significance

Pathogenic reviewed by expert panel P:21

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.910G>A p.Asp304Asn missense_variant Exon 6 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.910G>A p.Asp304Asn missense_variant Exon 6 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151924
Hom.:
0
Cov.:
32
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:
1
AN:
251318
Hom.:
0
AF XY:
0.00000736
AC XY:
1
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:
5
AN:
1457672
Hom.:
0
Cov.:
32
AF XY:
0.00000414
AC XY:
3
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:
8
AN:
151924
Hom.:
0
Cov.:
32
AF XY:
0.0000674
AC XY:
5
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:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:21
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:11
Nov 05, 2016
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 30, 2017
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 10, 2019
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 10, 2018
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 17, 2021
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

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. -

Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Nov 01, 1988
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Apr 13, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2016
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation;literature only

- -

Nov 28, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Familial hypercholesterolemia Pathogenic:4
May 03, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 02, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as Denver-2 and D283N. ClinVar contains an entry for this variant (Variation ID: 3692). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jan 05, 2021
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:2
Sep 26, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The LDLR c.910G>A (p.Asp304Asn) variant (also known as D283N, FH Denver-2) has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 34037665 (2021), 33740630 (2021), 24507775 (2014), 23064986 (2012), 22698793 (2012), 21418584 (2011), 12436241 (2002), 11810272 (2001)). This variant has also been reported in the compound heterozygous state in several pediatric cases with severe presentation (PMIDs: 36752612 (2023), 27678436 (2016), 30795984 (2019)). Functional studies indicate this variant causes significantly reduced LDLR activity (PMID: 1301956 (1992)). The frequency of this variant in the general population, 0.00012 (3/24946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Jun 14, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Homozygous familial hypercholesterolemia Pathogenic:1
Apr 06, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

LDLR-related disorder Pathogenic:1
Jul 17, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The LDLR c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant (also known as D283N) has been reported in heterozygous state to be causative for familial hypercholesterolemia (Callis et al. 1998. PubMed ID: 9664576; Fouchier et al. 2001. PubMed ID: 11810272; Amsellem et al. 2002. PubMed ID: 12436241; Luirink et al. 2019. PubMed ID: 30795984). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1
Aug 18, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;.;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D
M_CAP
Pathogenic
0.57
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M;.;.;.;.;M
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-4.2
D;D;D;D;D;D
REVEL
Pathogenic
0.88
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
D
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.

Other links and lift over

dbSNP: rs121908030; hg19: chr19-11218160; API