NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro) AND Familial hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Nov 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)]

NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)
Other names:
FH Alghero
  • NC_000019.10:g.11110760G>C
  • NG_009060.1:g.26380G>C
  • NM_000527.4:c.1049G>C
  • NM_000527.5:c.1049G>CMANE SELECT
  • NM_001195798.2:c.1049G>C
  • NM_001195799.2:c.926G>C
  • NM_001195800.2:c.545G>C
  • NM_001195803.2:c.668G>C
  • NP_000518.1:p.Arg350Pro
  • NP_000518.1:p.Arg350Pro
  • NP_001182727.1:p.Arg350Pro
  • NP_001182728.1:p.Arg309Pro
  • NP_001182729.1:p.Arg182Pro
  • NP_001182732.1:p.Arg223Pro
  • LRG_274t1:c.1049G>C
  • LRG_274:g.26380G>C
  • LRG_274p1:p.Arg350Pro
  • NC_000019.9:g.11221436G>C
  • P01130:p.Arg350Pro
  • c.1049G>C
Protein change:
LDLR-LOVD, British Heart Foundation: LDLR_001337; UniProtKB: P01130#VAR_005368; dbSNP: rs875989914
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000527.4:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.926G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.545G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.668G>C - missense variant - [Sequence Ontology: SO:0001583]


Familial hypercholesterolemia (FH)
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001349491Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Nov 17, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Color Health, Inc, SCV001349491.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)


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 tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. 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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 19, 2021

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