rs138315511

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4PS4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID:16542394, Denmark; at least 1 case with DLCN≥6 published in PMID:11810272, Netherlands; 1 case with DLCN criteria ≥6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia.PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023415/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:8B:2

Conservation

PhyloP100: 2.65

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 Uncertain_significance. Variant got 5 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1085A>C	p.Asp362Ala	missense_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 link	c.1085A>C	p.Asp362Ala	missense_variant	8/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152138

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:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251334

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135874

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461506

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74318

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:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:8Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Feb 19, 2016	MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN>=6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria >=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp362Ala variant in LDLR has been reported in 8 individuals (including 5 Danish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 27765764, 11810272, 16542394, 28145427), and has been identified in 0.01782% (23/129086) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138315511). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a benign variant, likely benign variant, VUS, and likely pathogenic variant (Variation ID: 36452). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces aspartic acid with alanine at codon 362 of the LDLR protein. This variant is also known as p.Asp341Ala in the mature protein. This variant alters a conserved aspartic acid residue in the EGF-like repeat B of the LDLR protein (a.a. 355-393), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 27765764, 33740630; Color internal data) and in one individual affected with isolated hypercholesterolemia (PMID: 33303402). This variant has been identified in 23/282712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2024	This missense variant replaces aspartic acid with alanine at codon 362 of the LDLR protein. This variant is also known as p.Asp341Ala in the mature protein. This variant alters a conserved aspartic acid residue in the EGF-like repeat B of the LDLR protein (a.a. 355-393), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 27765764, 33740630; Color internal data) and in one individual affected with isolated hypercholesterolemia (PMID: 33303402). This variant has been identified in 23/282712 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genomics, Royal Prince Alfred Hospital	Nov 28, 2022	The variant is present in multiple individuals with clinically diagnosed FH tested by this laboratory (50yo Male, DLCNS=6) and described in the literature, and is found at an extremely low frequency in control populations (gnomAD frequency 0.01782%). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 362 of the LDLR protein (p.Asp362Ala). This variant is present in population databases (rs138315511, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 11810272, 15823288, 16542394, 25487149, 27765764, 33303402). ClinVar contains an entry for this variant (Variation ID: 36452). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 23, 2024

Variant summary: LDLR c.1085A>C (p.Asp362Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251334 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.1085A>C has been reported in the literature in multiple individuals affected with Hypercholesterolemia (example, Benedek_2021, Brusgaard_2006, Damgaard_2005, Fouchier_2001, Gill_2021, Hollants_2012, Leren_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33955087, 16542394, 15823288, 11810272, 33303402, 22294733, 33740630). ClinVar contains an entry for this variant (Variation ID: 36452). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The p.D362A variant (also known as c.1085A>C and legacy p.D341A), located in coding exon 8 of the LDLR gene, results from an A to C substitution at nucleotide position 1085. The aspartic acid at codon 362 is replaced by alanine, an amino acid with dissimilar properties. This variant has been reported in individuals with familial hypercholesterolemia; however, some individuals had additional LDLR variants also detected, and clinical details were limited for some cases (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15, Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Rieck L et al. Clin Genet, 2020 11;98:457-467; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). This variant was also reported in an early onset myocardial infarction cohort in cases and control subjects (Do R et al. Nature, 2015 Feb;518:102-6). Furthermore, it has been reported in healthy population and exome cohorts where cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239; Shickh S et al. J Med Genet, 2021 04;58:275-283). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hypercholesterolemia

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;.;.;.;.

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.13

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

T;T;T;T;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.64

D;D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.74

N;.;.;.;.;N

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.4

D;D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.023

D;T;D;D;D;D

Sift4G

Uncertain

0.050

T;D;D;T;D;T

Polyphen

0.95

P;.;.;.;.;.

Vest4

0.39

MVP

1.0

MPC

0.33

ClinPred

0.35

GERP RS

3.3

Varity_R

0.22

gMVP

0.97

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

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