rs730882089

Positions:

Variant summary

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

The NM_000527.5(LDLR):c.827G>A(p.Cys276Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,096 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. C276G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.87

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 18 ACMG points.

PM1

In a domain LDL-receptor class A 7 (size 39) in uniprot entity LDLR_HUMAN there are 54 pathogenic changes around while only 7 benign (89%) 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 chr19-11107400-T-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 19-11107401-G-A is Pathogenic according to our data. Variant chr19-11107401-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11107401-G-A 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.827G>A	p.Cys276Tyr	missense_variant	6/18	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.827G>A	p.Cys276Tyr	missense_variant	6/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251426

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

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:

0.00000137

AC:

AN:

1459096

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725884

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces cysteine with tyrosine at codon 276 in the LDLR type A repeat 7 of the LDLR protein. This variant is also known as p.Cys255Tyr in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36229885). Multiple different variants affecting the same codon (p.Cys276Gly, p.Cys276Trp, p.Cys276Arg, p.Cys276Ser), are considered to be disease-causing (ClinVar variation ID: 251480, 251482, 251479, 183096), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2020

Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A_ repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); 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; Reported in the Human Gene Mutation Database with hypercholesterolaemia (HGMD) -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2020

The p.C276Y variant (also known as c.827G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 827. The cysteine at codon 276 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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 familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Ambry internal data). In addition, five different alterations located at the same amino acid position (p.C276F, p.C276S, p.C276R, p.C276G, p.C276W) have been detected in LDLR in families with hypercholesterolemia (Klanar G et al. J. Am. Coll. Cardiol., 2015 Sep;66:1250-1257; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Martín-Campos JM et al. J Clin Lipidol 2018 Sep;12:1452-1462; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was reported one time in population-based cohorts in the Genome Aggregation Database (gnomAD). 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

0.98

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.94

D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.0

H;.;.;.;.;H

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-9.3

D;D;D;D;D;D

REVEL

Pathogenic

0.94

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

0.98

MutPred

0.82

Loss of disorder (P = 0.0644);Loss of disorder (P = 0.0644);.;.;.;Loss of disorder (P = 0.0644);

MVP

1.0

MPC

0.88

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.99

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