rs770744861

Variant names:

• chr19-11120405-G-A
• rs770744861
• NM_000527.5:c.2023G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP1_Strong PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.853. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill criteria for FH (2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793; 1 case from PMID 27824480). PP1_Strong: Variant segregates with FH phenotype in at least 8 informative meioses from 4 families (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic): 5 affected family members have the variant and 3 unaffected family members do not have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA038175/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:2
• Conservation: PhyloP100: 7.89
• Publications: 2 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: Likely_pathogenic. The variant received 9 ACMG points.

• 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.2023G>A	p.Gly675Ser	missense_variant	Exon 14 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2023G>A	p.Gly675Ser	missense_variant	Exon 14 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249908 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461586 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

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

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 02, 2024

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.853. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill criteria for FH (2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793; 1 case from PMID 27824480). PP1_Strong: Variant segregates with FH phenotype in at least 8 informative meioses from 4 families (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic): 5 affected family members have the variant and 3 unaffected family members do not have the variant. -

Familial hypercholesterolemia Pathogenic:2 Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 675 of the LDLR protein (p.Gly675Ser). This variant is present in population databases (rs770744861, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11754108, 22698793, 27824480). This variant is also known as p.Gly654Ser. ClinVar contains an entry for this variant (Variation ID: 252173). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 31, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Gly654Ser in the mature protein) replaces glycine with serine at codon 675 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 11754108, 21310417, 22698793, 27824480). This variant has been identified in 1/249908 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.2023G>A (p.Gly675Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 249908 control chromosomes. c.2023G>A has been observed in individuals affected with Familial Hypercholesterolemia (Clingen Expert Panel, Kuhrova_2001, Gabcova_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11754108, 27824480). ClinVar contains an entry for this variant (Variation ID: 252173). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

May 04, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G675S variant (also known as c.2023G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2023. The glycine at codon 675 is replaced by serine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Jun 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in association with familial hypercholesterolemia (FH) in published literature (PMID: 11524740, 11754108); Also known as p.(G654S); This variant is associated with the following publications: (PMID: 25487149, 11524740, 11754108) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.;.;.;M
PhyloP100		7.9
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.85	P;.;.;.;.
Vest4		0.74
MutPred		0.91		Gain of glycosylation at G675 (P = 0.0225);Gain of glycosylation at G675 (P = 0.0225);.;.;Gain of glycosylation at G675 (P = 0.0225);
MVP		1.0
MPC		0.54
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.92
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs770744861; hg19: chr19-11231081;