NM_000527.5(LDLR):c.401G>T (p.Cys134Phe) AND Familial hypercholesterolemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 29, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000527.5(LDLR):c.401G>T (p.Cys134Phe)]

NM_000527.5(LDLR):c.401G>T (p.Cys134Phe)

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.401G>T (p.Cys134Phe)
Other names:
FH Alessandria
  • NC_000019.10:g.11105307G>T
  • NG_009060.1:g.20927G>T
  • NM_000527.4:c.401G>T
  • NM_000527.5:c.401G>TMANE SELECT
  • NM_001195798.2:c.401G>T
  • NM_001195799.2:c.278G>T
  • NM_001195800.2:c.314-2085G>T
  • NM_001195803.2:c.314-1258G>T
  • NP_000518.1:p.Cys134Phe
  • NP_000518.1:p.Cys134Phe
  • NP_001182727.1:p.Cys134Phe
  • NP_001182728.1:p.Cys93Phe
  • LRG_274t1:c.401G>T
  • LRG_274:g.20927G>T
  • LRG_274p1:p.Cys134Phe
  • NC_000019.9:g.11215983G>T
  • P01130:p.Cys134Phe
  • c.401G>T
Protein change:
LDLR-LOVD, British Heart Foundation: LDLR_001725; UniProtKB: P01130#VAR_062371; dbSNP: rs879254514
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001195800.2:c.314-2085G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1258G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.4:c.401G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.401G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.401G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.278G>T - 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)
SCV000909134Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Mar 12, 2019)
germlineclinical testing

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

SCV001212401Invitaecriteria provided, single submitter
(May 29, 2020)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]


This missense variant (also known as p.Cys113Phe in the mature protein and as FH Alessandria) is located in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Although functional assays have not been performed for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in three individuals with hypercholesterolemia in Italy, Germany, and Japan (PMID: 10978268 11462246 18718593, 23375686). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence this variant is classified as Likely Pathogenic.


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]

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]
See all PubMed Citations (12)

Details of each submission

From Color Health, Inc, SCV000909134.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001212401.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)


This sequence change replaces cysteine with phenylalanine at codon 134 of the LDLR protein (p.Cys134Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10978268, 11462246, 18718593). This variant is also known as C113F in the literature. ClinVar contains an entry for this variant (Variation ID: 251204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23375686, 11462246, 25921077, 10735632), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: May 10, 2021

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