NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) AND Familial hypercholesterolemia

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 20, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000791378.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)]

NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)
HGVS:
  • NC_000019.10:g.11116873C>T
  • NG_009060.1:g.32493C>T
  • NM_000527.4:c.1720C>T
  • NM_000527.5:c.1720C>TMANE SELECT
  • NM_001195798.2:c.1720C>T
  • NM_001195799.2:c.1597C>T
  • NM_001195800.2:c.1216C>T
  • NM_001195803.2:c.1339C>T
  • NP_000518.1:p.Arg574Cys
  • NP_000518.1:p.Arg574Cys
  • NP_001182727.1:p.Arg574Cys
  • NP_001182728.1:p.Arg533Cys
  • NP_001182729.1:p.Arg406Cys
  • NP_001182732.1:p.Arg447Cys
  • LRG_274t1:c.1720C>T
  • LRG_274:g.32493C>T
  • NC_000019.9:g.11227549C>T
  • NM_000527.4(LDLR):c.1720C>T
  • P01130:p.Arg574Cys
  • c.1720C>T
  • p.(Arg574Cys)
Protein change:
R406C
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000232; UniProtKB: P01130#VAR_072851; dbSNP: rs185098634
NCBI 1000 Genomes Browser:
rs185098634
Molecular consequence:
  • NM_000527.4:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1597C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1339C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000752408Invitaecriteria provided, single submitter
Pathogenic
(Oct 20, 2020)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV001349170Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Jan 2, 2019)
germlineclinical testing

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

Description

This missense variant (also known as p.Arg553Cys in the mature protein) is located in the LDLR type B repeat 5 of the EGF precursor homology 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 RNA splicing. A high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in ten or more individuals affected with familial hypercholesterolemia (PMID: 11462246, 19446849, 20145306, 23375686, 26892515). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 9/277230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although additional studies are required to determine the pathogenicity of this variant conclusively, this variant is classified as Likely Pathogenic based on current evidence.

SCV001349170

Summary from all submissions

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

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]
PMID:
11462246

The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia.

Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, Bertolini S.

J Pediatr. 2009 Aug;155(2):199-204.e2. doi: 10.1016/j.jpeds.2009.02.022. Epub 2009 May 15.

PubMed [citation]
PMID:
19446849
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000752408.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change replaces arginine with cysteine at codon 574 of the LDLR protein (p.Arg574Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs185098634, ExAC 0.02%). This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 11462246, 19446849, 26892515), probable hypercholesterolemia (PMID: 23375686, 20145306), and myocardial infarction (PMID: 25487149). ClinVar contains an entry for this variant (Variation ID: 183123). 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. Different missense substitutions at this codon (p.Arg574His, p.Arg574Ser, p.Arg574Leu) have been reported in several individuals affected with hypercholesterolemia (PMID: 28028493, 20018285, 22698793). This suggests that the arginine residue is critical for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.

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

From Color Health, Inc, SCV001349170.1

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

Last Updated: Oct 7, 2021

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