rs755757866

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.1019G>A(p.Cys340Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,524 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. C340L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 9.65

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a domain EGF-like 1 (size 39) in uniprot entity LDLR_HUMAN there are 56 pathogenic changes around while only 3 benign (95%) 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 chr19-11110729-TGC-TTG is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.997

PP5

Variant 19-11110730-G-A is Pathogenic according to our data. Variant chr19-11110730-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11110730-G-A is described in Lovd as [Pathogenic]. Variant chr19-11110730-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.1019G>A	p.Cys340Tyr	missense_variant	7/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1019G>A	p.Cys340Tyr	missense_variant	7/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461524

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727064

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt disulfide bridge between Cys340 and Cys352. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, flagged submission	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 14, 2023	The c.1019G>A (p.Cys340Tyr) variant in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in in at least ten unrelated individuals with Familial Hypercholesterolemia (FH) (PMID:34834584, 30592178, 27824480, 15241806, 35560019, 33391333). Another study reports that this variant has been identified in three Slovak probands with FH and three relatives, however the phenotype of the relatives are not clear (PMID: 27824480). This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In-silico computational prediction tools suggest that the p.Cys340Tyr variant may have deleterious effect on the protein function (REVEL score: 0.923). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251600). Therefore, the c.1019G>A (p.Cys340Tyr) variant in the LDLR gene is classified as likely pathogenic. -

Familial hypercholesterolemia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 25, 2020	This missense variant (also known as p.Cys319Tyr in the mature protein) replaces cysteine with tyrosine at codon 340 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). Although functional studies have not been performed for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in multiple individuals diagnosed with familial hypercholesterolemia (PMID: 15241806, 27824480). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 340 of the LDLR protein (p.Cys340Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 27824480, 30592178). ClinVar contains an entry for this variant (Variation ID: 251600). 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%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 22, 2021

The p.Cys340Tyr variant in LDLR has been reported in 5 individuals with hypercholesterolemia and segregated with disease in 3 affected relatives (Mozas 2014, Gabcova 2017, Chan 2019). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 251600). Three additional variants at this codon have been reported in individuals with hypercholesterolemia (p.Cys340Phe, p.Cys340Trp, and p.Cys340Leu), suggesting that changes at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that the p.Cys340Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Supporting, PM5_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.1019G>A (p.C340Y) 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 1019, causing the cysteine (C) at amino acid position 340 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, 2002). This variant (also referred to as p.C319Y) has been detected in several individuals with FH or from FH cohorts (Mozas, 2004; Gabová, 2017; Chan, 2019). Internal 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

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.98

D;.;.;.;.;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

1.0

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;.;.;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-11

D;D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

1.0

MutPred

0.99

Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;.;.;Loss of sheet (P = 0.1907);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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.

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