rs879254754

Variant names:

• chr19-11110724-G-A
• rs879254754
• NM_000527.5:c.1013G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11110724-G-A
• chr19-11110724-G-C
• chr19-11110724-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.1013G>A​(p.Cys338Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C338W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.65
• Publications: 5 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 3 benign, 15 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 chr19-11110725-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 986739.Status of the report is no_assertion_criteria_provided, 0 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, 0.997
• PP5: Variant 19-11110724-G-A is Pathogenic according to our data. Variant chr19-11110724-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251595.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.1013G>A	p.Cys338Tyr	missense_variant	Exon 7 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1013G>A	p.Cys338Tyr	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disrupt disulfide bridge between Cys325 and Cys338. -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 28, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1013G>A (p.Cys338Tyr) missense variant results in the substitution of cysteine at amino acid position 338 with tyrosine. This variant has been identified in individuals with a phenotype consistent with familial hypercholesterolemia, and has been shown to segregate with disease (PMID: 10924730; 34037665). A functional study conducted in patient cells demonstrated that this variant impacts protein function (PMID: 10924730). This variant affects one of 60 highly conserved cysteine residues that are critical for protein folding and function (PMID: 34906454). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1013G>A (p.Cys338Tyr) variant is classified as likely pathogenic for familial hypercholesterolemia. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dyslipidemia Pathogenic:1

Jun 14, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 13, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM5, PM2, PM3_supporting, PS3_supporting, PP3, PP1 -

Cardiovascular phenotype Pathogenic:1

Jan 02, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C338Y pathogenic mutation (also known as c.1013G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1013. The cysteine at codon 338 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH), and reduced LDL binding was demonstrated in a study of patient skin fibroblasts (Nauck MS et al. Atherosclerosis, 2000;151:525-34; Dušková L et al. Atherosclerosis, 2011;216:139-45). 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 L et al. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Rudenko G et al. Science. 2002;298(5602):2353-8). In addition, alterations at the same amino acid position (C338G, C338R, and C338S) have also been reported in association with FH (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Varret M et al. Nucleic Acids Res., 1998;26:248-52; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995;15:1713-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Mar 19, 2024

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 338 of the LDLR protein (p.Cys338Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10924730). It has also been observed to segregate with disease in related individuals. This variant is also known as p.C317T. ClinVar contains an entry for this variant (Variation ID: 251595). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 10924730). 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.Cys338 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8568489, 10735632, 10924730, 24420163), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;.;H
PhyloP100		9.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D
REVEL	Pathogenic	0.93
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		0.98
MutPred		0.99		Loss of ubiquitination at K333 (P = 0.1264);Loss of ubiquitination at K333 (P = 0.1264);.;.;.;Loss of ubiquitination at K333 (P = 0.1264);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		1.0
gMVP		0.99
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: rs879254754; hg19: chr19-11221400;