rs761954844

Variant summary

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

The NM_000527.5(LDLR):​c.986G>A​(p.Cys329Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,760 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C329F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12B:1

Conservation

PhyloP100: 9.68
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 18 ACMG points.

PM1
In a disulfide_bond (size 11) in uniprot entity LDLR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) 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 chr19-11110697-G-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 19-11110697-G-A is Pathogenic according to our data. Variant chr19-11110697-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11110697-G-A is described in Lovd as [Pathogenic]. Variant chr19-11110697-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.986G>A p.Cys329Tyr missense_variant 7/18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.986G>A p.Cys329Tyr missense_variant 7/181 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152172
Hom.:
0
Cov.:
32
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250998
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
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:
0.00000411
AC:
6
AN:
1461588
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727096
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
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:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7Benign:1
Likely benign, flagged submissionclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, no assertion criteria providedclinical testingCardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley HospitalNov 17, 2008- -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Centre for Cardiovascular Surgery and TransplantationNov 05, 2016Disrupt disulfide bridge between Cys318 and Cys329. -
Likely pathogenic, criteria provided, single submitterclinical testingRobarts Research Institute, Western University-- -
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 22, 2020The p.Cys329Tyr variant in LDLR has been reported in at least 25 individuals (including 17 Taiwanese, 2 Russian, 2 Chinese, 1 Filipino, and 1 Czech individuals) with Familial Hypercholesterolemia (PMID: 22353362, 9763532, 11810272, 15701167, 16205024, 27765764, 22698793), and has been identified in 0.01003% (2/19938) of East Asian chromosomes and 0.005645% (2/35428) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761954844). 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 as a likely benign variant, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 226344). In vitro functional studies with transfected COS cells provide some evidence that the p.Cys329Tyr variant may impact LDL receptor activity (PMID: 26608663). 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. One additional variant with a different amino acid change at the same position (p.Cys329Phe) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 251586). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_supporting, PM5_supporting, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submittercuration;literature onlyCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 2016- -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxApr 30, 2024Not 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; Also known as p.(C308Y); This variant is associated with the following publications: (PMID: 31706281, 30592178, 33269076, 32423031, 30270359, 32041611, 33303402, 33740630, 33994402, 9452118) -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 23, 2021The LDLR c.986G>A; p.Cys329Tyr variant (rs761954844), also known as Cys308Tyr, is reported in the literature in multiple individuals and families affected with familial hypercholesterolemia (Alver 2019, Mak 1998, Miroshnikova 2021, Jiang 2015). Functional analyses show the variant protein had LDLR activity of ~30% of wildtype (Jiang 2015). This variant is reported in ClinVar (Variation ID: 226344) and is found in the general population with an overall allele frequency of 0.003% (7/282402 alleles) in the Genome Aggregation Database. The cysteine at codon 329 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.965). Based on available information, this variant is considered to be pathogenic. References: Alver M et al. Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia. Genet Med. 2019 May;21(5):1173-1180. PMID: 30270359. Mak YT et al. Possible common mutations in the low density lipoprotein receptor gene in Chinese. Hum Mutat. 1998;Suppl 1:S310-3. PMID: 9452118. Miroshnikova VV et al. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. Biomed Rep. 2021 Jan;14(1):15. PMID: 33269076. Jiang L et al. The distribution and characteristics of LDL receptor mutations in China: A systematic review. Sci Rep. 2015 Nov 26;5:17272. PMID: 26608663. -
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 13, 2024This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 329 of the LDLR protein (p.Cys329Tyr). This variant is present in population databases (rs761954844, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452118, 30270359, 30592178, 31706281). It has also been observed to segregate with disease in related individuals. This variant is also known as C308Y. ClinVar contains an entry for this variant (Variation ID: 226344). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterresearchLaboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive MedicineJul 17, 2024Based on the ACMG/AMP 2015 guidelines (Richards 2015), p.Cys329Tyr variant has the following pathogenicity criteria: PS3 - an in vitro functional study shows that the presence of this variant reduces LDL receptor activity to 31% in transfected COS cells (Chang 2003); PM1 - located in a critical and well-established functional domain of the LDLR (EGF-A) (Galicia-Garcia 2020); PM2 - detected in control samples of gnomAD v4.1.0 with a frequency of 0.0006197%; PP1 - segregated with FH in 4 relatives in 2 families (data from the Laboratory of Molecular Genetics, Moscow, Russia); PP3; PP4 (registered in patients with FH). According to the ClinGen guidelines for LDLR variant classification (Chora 2022): PS4 - variant is found in ≥10 unrelated FH cases, including in Russia (Jiang 2015 (n = 26), Meshkov 2021 and Vasilyev 2022 (n = 13)); PS3_Moderate - meets level 2 pathogenic functional study criteria (Chang 2003); PM1 - changes in 1 of 60 highly conserved cysteine residues (p.Cys329) (Chora 2022); PM2 - has a PopMax MAF ≤ 0.0002 (0.02%) in gnomAD (0.0006197% v4.1.0 gnomAD); PP1_Moderate - segregates with phenotype in 4 informative meioses in 2 family (data from the Laboratory of Molecular Genetics, Moscow, Russia); PP3 - REVEL score 0.965 (Liu 2011, Liu 2020); PP4 - identified in 8 probands with FH (diagnosis based on DLCN-criteria (Meshkov 2021)). Based on a combination of criteria, this variant is pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 18, 2023The c.986G>A (p.C329Y) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 986, causing the cysteine (C) at amino acid position 329 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/282402) total alleles studied. The highest observed frequency was 0.01% (2/19938) of East Asian alleles. This alteration, also referred to as p.C308Y, has been described in multiple individuals with familial hypercholesterolemia (FH) (Mak, 1998; Fouchier, 2001; Punzalan, 2005; Zakharova, 2005; Chiou, 2010; Tichý, 2012; Fan, 2015). This alteration has also been reported to segregate with the disease in one family, and in vitro studies suggested that the alteration led to reduced surface protein expression and ligand binding (Chang, 2003). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in FH (Villéger, 2002). Structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;.;.;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
1.0
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.5
H;.;.;.;.;H
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-11
D;D;D;D;D;D
REVEL
Pathogenic
0.96
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
0.99
MutPred
0.96
Gain of catalytic residue at C329 (P = 0.0565);Gain of catalytic residue at C329 (P = 0.0565);.;.;.;Gain of catalytic residue at C329 (P = 0.0565);
MVP
1.0
MPC
1.0
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.99
gMVP
1.0

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: rs761954844; hg19: chr19-11221373; API