rs879254801

Variant names:

• chr19-11111583-G-A
• rs879254801
• NM_000527.5:c.1130G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11111583-G-A
• chr19-11111583-G-C
• chr19-11111583-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.1130G>A​(p.Cys377Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,614 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. C377R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.77
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain 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 chr19-11111582-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1727785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 19-11111583-G-A is Pathogenic according to our data. Variant chr19-11111583-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1130G>A	p.Cys377Tyr	missense_variant	Exon 8 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1130G>A	p.Cys377Tyr	missense_variant	Exon 8 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461614 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 22, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 24, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1130G>A; p.Cys377Tyr variant (rs879254801), also known as Cys356Tyr in legacy nomenclature, is reported in the literature in the heterozygous and compound heterozygous states in numerous individuals affected with familial hypercholesterolemia (Ekstrom 1998, Benedek 2021, Gabcova 2017, Marco-Benedi 2022, Rieck 2020, Wang 2018). This variant is also reported in ClinVar (Variation ID: 251681) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Arg, Gly, Phe, Ser) have been reported in individuals with familial hypercholesterolemia and are considered to be disease causing (Bertolini 2020, Bertolini 2013, Gabcova 2017, Wu 2014). Computational analyses predict that this variant is deleterious (REVEL: 0.984). Based on the available information, this variant is considered to be pathogenic. References: Ekstrom U et al. Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response. Eur J Clin Invest. 1998 Sep;28(9):740-7. PMID: 9767373. Benedek P et al. Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. J Intern Med. 2021 Aug;290(2):404-415. PMID: 33955087. Bertolini S et al. Italian Study Group of Homozygous Familial Hypercholesterolemia. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Bertolini S et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. PMID: 23375686. Gabcova D et al. The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. Physiol Res. 2017 Mar 31;66(1):75-84. PMID: 27824480. Marco-Benedi V et al. Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. Atherosclerosis. 2022 May;349:211-218. PMID: 34456049. Rieck L et al. Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. Clin Genet. 2020 Nov;98(5):457-467. PMID: 32770674. Wang F et al. Genetic analysis in a compound heterozygote family with familial hypercholesterolemia. Mol Med Rep. 2018 Jun;17(6):8439-8449. PMID: 29693183. Wu WF et al. Use of targeted exome sequencing in genetic diagnosis of Chinese familial hypercholesterolemia. PLoS One. 2014 Apr 10;9(4):e94697. PMID: 24722143. -

Cardiovascular phenotype Pathogenic:1

Jun 09, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C377Y pathogenic mutation (also known as c.1130G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1130. The cysteine at codon 377 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the EGF-like B domain. This alteration, also described as p.C356Y, has been identified in several individuals from familial hypercholesterolemia (FH) cohorts (Ekström U et al. Eur. J. Clin. Invest. 1998;28:740-7, Mozas P et al. Hum. Mutat. 2004;24:187, Vandrovcova J et al. Genet. Med. 2013;15:948-57). In addition, alterations involving the same amino acid position, p.C377S (c.1130G>C), p.C377G (c.1129T>G) and p.C377F (c.1130G>T) have been reported in individuals with FH (Bertolini S et al. Atherosclerosis. 2013;227: 342-8, Wu WF et al. PLoS ONE 2014; 9:e94697, Romano M et al, J. Lipid Res. 2011; 52:2095-100). Pathogenic LDLR alterations 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 (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 EGF-like 2 domain (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 377 of the LDLR protein (p.Cys377Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9767373, 23680767, 27824480, 32770674). This variant is also known as p.C356Y. ClinVar contains an entry for this variant (Variation ID: 251681). 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). This variant disrupts the p.Cys377 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24722143, 29693183). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.9	H;.;.;.;.;H
PhyloP100		9.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-10	D;D;D;D;D;D
REVEL	Pathogenic	0.98
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		0.96
MutPred		0.97		Loss of methylation at K376 (P = 0.0139);Loss of methylation at K376 (P = 0.0139);.;.;.;Loss of methylation at K376 (P = 0.0139);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879254801; hg19: chr19-11222259;