rs879254747

Variant names:

• chr19-11110688-C-G
• rs879254747
• NM_000527.5:c.977C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11110688-C-G
• chr19-11110688-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PS4_Supporting PP3 PP4 PP1_Strong PS3

This summary comes from the ClinGen Evidence Repository: PP1_strong: Variant segregates with FH phenotype in at least 28 informative meiosis (minimum 2) from 9 families from different labs (Laboratory of Genetics and Molecular Cardiology). PS3: PMID:32015373. Level 1 assay. Heterologous cells (CHO), FACS assays. Normal cell surface LDLR (90%), 50% binding and 48% uptake.PS4_supporting: variant meets PM2 and is identified in 1 index case who fulfills SB criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and 1 index case with DLCN >6 from PMID 30270055, Corral et al., 2018 (Argentina) so PS4_Supporting is met PM2: No population data was found for this variant in gnomAD (gnomAD version 2.1.1). PP3: REVEL = 0.927. PP4: Variant meets PM2 and is identified in 1 index case who fulfils SB for FH from different labs (Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and Laboratory of Genetics and Molecular Cardiology). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585235/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 5.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.977C>G	p.Ser326Cys	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.977C>G	p.Ser326Cys	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727076

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: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Apr 05, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PP1_strong: Variant segregates with FH phenotype in at least 28 informative meiosis (minimum 2) from 9 families from different labs (Laboratory of Genetics and Molecular Cardiology). PS3: PMID: 32015373. Level 1 assay. Heterologous cells (CHO), FACS assays. Normal cell surface LDLR (90%), 50% binding and 48% uptake. PS4_supporting: variant meets PM2 and is identified in 1 index case who fulfills SB criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and 1 index case with DLCN >6 from PMID 30270055, Corral et al., 2018 (Argentina) so PS4_Supporting is met PM2: No population data was found for this variant in gnomAD (gnomAD version 2.1.1). PP3: REVEL = 0.927. PP4: Variant meets PM2 and is identified in 1 index case who fulfils SB for FH from different labs (Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and Laboratory of Genetics and Molecular Cardiology). -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Iberoamerican FH Network

Significance: Likely 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

- -

Familial hypercholesterolemia Pathogenic:2

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 326 of the LDLR protein (p.Ser326Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12820708, 23375686, 23815734, 25463123). This variant is also known as S305C. ClinVar contains an entry for this variant (Variation ID: 251581). 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 disrupts the p.Ser326 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11668640), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jan 09, 2025

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.977C>G p.(Ser326Cys) missense variant has been reported in at least 4 unrelated FH probands meeting clinical criteria, including patients where alternative causes of high cholesterol were excluded (PS4_SUPPORTING, PP4_SUPPORTING; PMIDs 23375686, 22698793, 30270055, ClinGen FH VCEP data) and has been seen to segregate with FH phenotype in >=6 informative meiosis (PP1_STRONG; ClinGen FH VCEP data, PMID: 23815734). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). This variant meets level 1 pathogenic functional study criteria with <70% of wild-type activity in LDL binding and LDL internalisation in heterologous cells (CHO) (PS3_STRONG; PMID: 32015373). REVEL score is 0.927 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;H
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.87
MutPred		0.93		Loss of disorder (P = 0.0983);Loss of disorder (P = 0.0983);.;.;.;Loss of disorder (P = 0.0983);
MVP		1.0
MPC		0.77
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

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

Other links and lift over

dbSNP: rs879254747; hg19: chr19-11221364;