NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro) AND Familial hypercholesterolemia 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 3, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [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 1 (FHCL1)
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000268596Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospitalno assertion criteria providedPathogenic
(Jun 5, 2008)
germlineclinical testing

SCV000295162LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely pathogenic
(Mar 25, 2016)
germlineliterature only

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

Citation Link,

SCV000627011Invitaecriteria provided, single submitter
Uncertain significance
(Mar 3, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes4not providednot provided1not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom.

Webb JC, Sun XM, McCarthy SN, Neuwirth C, Thompson GR, Knight BL, Soutar AK.

J Lipid Res. 1996 Feb;37(2):368-81.

PubMed [citation]

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268596.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences

From LDLR-LOVD, British Heart Foundation, SCV000295162.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Invitae, SCV000627011.1

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


This sequence change replaces arginine with proline at codon 350 of the LDLR protein (p.Arg350Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in the heterozygous state in two siblings affected with hypercholesterolemia in combination with a likely pathogenic variant in the other chromosome (PMID: 9026534). It has also been reported in the heterozygous state in an individual affected with hypercholesterolemia (PMID: 19837725). ClinVar contains an entry for this variant (Variation ID: 226343). Experimental studies have shown that this missense change causes LDLR protein misfolding and reduced expression at the cell surface (PMID: 15100232). In summary, this variant is a rare missense change that has been shown to affect protein function and it has been reported in affected individuals. However, additional genetic and/or functional data is necessary to classify this variant conclusively. For these reasons, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Jun 18, 2021

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