NM_000527.5(LDLR):c.1721G>A (p.Arg574His) AND Familial hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Nov 11, 2019)

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:
RCV000791382.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1721G>A (p.Arg574His)]

NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

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.1721G>A (p.Arg574His)
HGVS:
  • NC_000019.10:g.11116874G>A
  • NG_009060.1:g.32494G>A
  • NM_000527.4:c.1721G>A
  • NM_000527.5:c.1721G>AMANE SELECT
  • NM_001195798.2:c.1721G>A
  • NM_001195799.2:c.1598G>A
  • NM_001195800.2:c.1217G>A
  • NM_001195803.2:c.1340G>A
  • NP_000518.1:p.Arg574His
  • NP_000518.1:p.Arg574His
  • NP_001182727.1:p.Arg574His
  • NP_001182728.1:p.Arg533His
  • NP_001182729.1:p.Arg406His
  • NP_001182732.1:p.Arg447His
  • LRG_274t1:c.1721G>A
  • LRG_274:g.32494G>A
  • LRG_274p1:p.Arg574His
  • NC_000019.9:g.11227550G>A
  • P01130:p.Arg574His
  • c.1721G>A
Protein change:
R406H
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000233; UniProtKB: P01130#VAR_072852
Molecular consequence:
  • NM_000527.4:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1598G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1217G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1340G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000836468Invitaecriteria provided, single submitter
Likely pathogenic
(Nov 11, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001355014Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Oct 14, 2019)
germlineclinical testing

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

Description

This missense variant (also known as p.Arg553His in the mature protein) replaces arginine with histidine at codon 574 in the LDLR type B repeat 5 of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 20018285, 23375686, 25461735). This variant has been identified in 9/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant, p.Arg574Cys, is known to be pathogenic (Clinvar variation ID 183123), indicating that arginine at this codon position is important for LDLR function. Based on the available evidence, this variant is classified as Likely Pathogenic.

SCV001355014

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 (7)

Details of each submission

From Invitae, SCV000836468.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with histidine at codon 574 of the LDLR protein (p.Arg574His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs777188764, ExAC 0.01%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 20018285, 25461735, Invitae). ClinVar contains an entry for this variant (Variation ID: 251996). 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. Variants that disrupt the p.Arg574 amino acid residue in LDLR have been observed in affected individuals (PMID: 11462246, 19446849, 26892515, 20018285, 25461735, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Color Health, Inc, SCV001355014.1

#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: May 10, 2021

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