chr19-11107512-G-A

Position:

chr19-11107512-G-A

Variant summary

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

The NM_000527.5(LDLR):c.938G>A(p.Cys313Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,607,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C313G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

Splicing: ADA: 0.9228

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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 disulfide_bond (size 17) in uniprot entity LDLR_HUMAN there are 36 pathogenic changes around while only 3 benign (92%) 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 chr19-11107511-T-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 19-11107512-G-A is Pathogenic according to our data. Variant chr19-11107512-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11107512-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.938G>A	p.Cys313Tyr	missense_variant, splice_region_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.938G>A	p.Cys313Tyr	missense_variant, splice_region_variant	6/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000687

AC:

AN:

1455594

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

724086

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:

0.00000903

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 25, 2018	This c.938G>A (p.Cys313Tyr) variant in the LDLR gene has been reported in multiple familial hypercholesterolemia patients [PMID: 9259195, 11857755, 11810272] but not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. Multiple in silico predictions suggest this cysteine to tyrosine is deleterious. Multiple variants causing cysteine at amino acid position 313 change to other amino acids have been reported as disease-causing in literature [PMID: 19318025, 15823288, 11257257]. Based upon above evidences, c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 11, 2023	The c.938G>A (p.Cys313Tyr) variant of the LDLR gene has been identified in heterozygous status in multiple (>10) unrelated individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 9259195, 9698020, 11040093, 11810272, 11857755, 27680772, 33269076, 23833242, 22883975, 17094996). This variant has also been identified in compound heterozygous status in two individuals with FH (PMID: 21382890). In-silico computational prediction tools suggest that the p.Cys313Tyr variant may have deleterious effect on protein function (REVEL score: 0.979). This variant affects one of the sixty highly conserved cysteine residues located within an LDLR class A 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). 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: 226339). Other amino acid substitutions at the same codon (p.Cys313Gly, p.Cys313Trp) have been classified as likely pathogenic by several ClinVar submitters (ClinVar ID: 251538, 251540). Therefore, the c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Mar 18, 2010	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 15, 2024	The LDLR c.938G>A (p.Cys313Tyr) variant has been reported in the published literature in numerous individuals with familial hypercholesterolemia (FH) (PMIDs: 33269076 (2021), 27680772 (2016), 23833242 (2013), 22883975 (2012), 19717150 (2010), 17094996 (2007), 15556094 (2004), 11040093 (2000), 9698020 (1998), 9259195 (1997)). Other missense variants affecting this codon (p.Cys313Gly, p.Cys313Arg) have also been reported as deleterious in individuals with FH (PMIDs: 35480308 (2022), 19318025 (2009)). The frequency of the c.938G>A (p.Cys313Tyr) variant in the general population, 0.0000066 (1/152106 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 08, 2020	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2019

The p.Cys313Tyr variant in LDLR (also described as p.Cys292Tyr in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), of which 2 are in the compound heterozygous state (Day 1997, Thiart 2000, Fouchier 2001, Bunn 2002, Van der Graaf 2011, Martin 2016). It has also been reported in ClinVar (Variation ID: 226339) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Cys131Tyr variant may impact the protein. This variant is located in the last three bases of the exon, which is part of the 5â€™ splice region. Computational tools do not suggest an impact to splicing. Additionally, other missense variants at this amino acid position (p.Cys313Arg, p.Cys313Gly and p.Cys313Trp) have been reported in individuals with familial hypercholesterolemia (Human Gene Mutation Database: Stenson 2017), suggesting that changes at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys313Tyr variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PM2, PP3, PM5_Supporting. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2018

This sequence change replaces cysteine with tyrosine at codon 313 of the LDLR protein (p.Cys313Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA domain 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 domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Other missense substitutions at this codon (p.Cys313Arg) have been reported in individuals affected with hypercholesterolemia (PMID: 19318025). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 9259195,¬†9698020, 11810272, 11857755). This variant is also known as p.Cys292Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 226339). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.3

H;.;.;.;.;H

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-9.3

D;D;D;D;D;D

REVEL

Pathogenic

0.98

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

0.90

MutPred

0.97

Gain of phosphorylation at C313 (P = 0.0685);Gain of phosphorylation at C313 (P = 0.0685);.;.;.;Gain of phosphorylation at C313 (P = 0.0685);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.050

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