19-11110760-G-C

Variant names:

• chr19-11110760-G-C
• rs875989914
• NM_000527.5:c.1049G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP1_Moderate PM2 PP4 PS3_Moderate PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000527.4(LDLR): c.1049G>C (p.Arg350Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting, PP1_Moderate, PP4, and PS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: This variant is absent from gnomAD (gnomAD v2.1.1).. PS4_Supporting: Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. PP1_Moderate: Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.. PS3_moderate: Level 2 assays: PMID 15100232Heterologous cells (CHO) ACS, WB and NMR Spectroscopy<10% cell surface LDLR, 65% binding, (WB), ~10% expression LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576296/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 0.384
• Publications: 6 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 8 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1049G>C	p.Arg350Pro	missense	Exon 7 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1049G>C	p.Arg350Pro	missense	Exon 7 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.926G>C	p.Arg309Pro	missense	Exon 6 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1049G>C	p.Arg350Pro	missense	Exon 7 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1307G>C	p.Arg436Pro	missense	Exon 7 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1049G>C	p.Arg350Pro	missense	Exon 7 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461052 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726844

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52788

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

Sep 11, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 8 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar). Additional information: Variant is predicted to result in a missense amino acid change from Arg to Pro; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268); Alternative amino acid change(s) at the same position are present in gnomAD (highest allele count: v4: 11 heterozygote(s), 0 homozygote(s)); Other missense variant(s) comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg350Gln) has been classified as a VUS by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar). Additionally, p.(Arg350Gly) has been classified as likely pathogenic and as a VUS by clinical laboratories in ClinVar; Variant is not located in an established domain, motif, hotspot or informative constraint region; Missense variant with inconclusive in silico prediction and uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890); The condition associated with this gene has incomplete penetrance (PMID: 24404629); Inheritance information for this variant is not currently available in this individual.

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.4(LDLR): c.1049G>C (p.Arg350Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting, PP1_Moderate, PP4, and PS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: This variant is absent from gnomAD (gnomAD v2.1.1). . PS4_Supporting: Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France . PP1_Moderate: Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. . PS3_moderate: Level 2 assays: PMID 15100232 Heterologous cells (CHO) ACS, WB and NMR Spectroscopy <10% cell surface LDLR, 65% binding, (WB), ~10% expression

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Nov 14, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Arg329Pro in the mature protein) replaces arginine with proline at codon 350 in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes LDLR protein misfolding and significant reduction in protein activity (PMID: 9026534, 15100232). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 31106925). This variant has also been reported in compound heterozygosity with a pathogenic variant p.Cys248Tyr in an individual affected with familial hypercholesterolemia (PMID: 9026534). The proband's affected sister was also compound heterozygous. The proband's affected father was heterozygous for this variant, and the proband's affected mother was heterozygous for p.Cys248Tyr (PMID: 9026534). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been shown to disrupt LDLR function and demonstrated to segregate with disease in a family study. Based on available evidence, this variant is classified as Likely Pathogenic.

Apr 05, 2022

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR p.Arg350Pro (originally Arg329Pro, FH Alghero) missense variant has previously been identified in multiple cohorts of familial hypercholesterolemia patients. In vitro studies demonstrated that LDLR p.Arg350Pro affected protein folding and surface expression, resulting in decreased LDL-receptor activity (PMID: 15100232, 9026534).

Familial hypercholesterolemia Pathogenic:3

Sep 25, 2025

Clinical Genomic Analysis (GENYSIS) Core, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

LDLR c.1049G>C, p.(Arg350Pro), is a missense variant predicted to alter a single conserved amino acid in the encoded protein from an arginine to a proline. As this variant has been reported to segregate with FH in multiple affected families, and functional studies demonstrate that the c.1049G>C variant has a damaging effect on the protein product, the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel have classified it as likely pathogenic.

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 350 of the LDLR protein (p.Arg350Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9026534, 19837725; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 226343). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 15100232). This variant disrupts the p.Arg350 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 31106925), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

May 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with proline at codon 350 in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Arg329Pro in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Experimental functional studies have shown that this variant causes LDLR protein mis-folding and a significant reduction in protein activity (PMID: 9026534, 15100232). This LDLR variant has been reported in several heterozygous individuals affected with familial hypercholesterolemia (PMID: 9026534, 31106925; ClinVar SCV004022403.1; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two related individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 9026534). It has been shown that this variant segregates with the familial hypercholesterolemia phenotype in five individuals across three families (ClinVar SCV004022403.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

not provided Pathogenic:2

Jun 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1049G>C (p.Arg350Pro) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia including at least one case with another LDLR variant (p.Cys248Tyr) in trans (PMIDs: 9026534 (1996), 17094996 (2007), and 22883975 (2012)). Experimental studies have shown that this variant results in protein misfolding, reduced cell-surface expression, decreased LDL-receptor activity (PMIDs: 9026534 (1996) and 15100232 (2004)), and impaired binding interaction with PCSK9 (PMID: 24103783 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152190 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.

Feb 13, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in protein misfolding and reduced cell-surface expression compared to the wild-type protein (Boswell et al., 2004) as well as results in impaired binding interaction with PCSK9 (Gu et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R329P; This variant is associated with the following publications: (PMID: 17094996, 31106925, 9026534, 24103783, 19837725, 15556093, 11435110, 32719484, 22883975, 15100232)

Cardiovascular phenotype Pathogenic:1

Feb 19, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R350P pathogenic mutation (also known as c.1049G>C and p.R329P), located in coding exon 7 of the LDLR gene, results from a G to C substitution at nucleotide position 1049. The arginine at codon 350 is replaced by proline, an amino acid with dissimilar properties. This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia, including in trans co-occurrence with another LDLR variant in individual(s) with severe hypercholesterolemia, and segregated with disease in at least one family (Hendry WG et al. J R Soc Med, 1985 Apr;78:334-5; Webb JC et al. J Lipid Res, 1996 Feb;37:368-81; Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; external data; Ambry internal data). In an assay testing LDLR function, this variant showed a functionally abnormal result (Boswell EJ et al. J Biol Chem, 2004 Jul;279:30611-21). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep, 2011 Dec;12:1300-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.38
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.91	P
Vest4		0.65
MutPred		0.83		Gain of disorder (P = 0.1387)
MVP		1.0
MPC		0.74
ClinPred		0.95	D
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.99
Mutation Taster		=2/98	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: rs875989914; hg19: chr19-11221436;