NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro) AND Familial hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Jan 23, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000775075.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro)]

NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro)

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.1745T>C (p.Leu582Pro)
Other names:
NP_000518.1:p.L582P
HGVS:
  • NC_000019.10:g.11116898T>C
  • NG_009060.1:g.32518T>C
  • NM_000527.5:c.1745T>CMANE SELECT
  • NM_001195798.2:c.1745T>C
  • NM_001195799.2:c.1622T>C
  • NM_001195800.2:c.1241T>C
  • NM_001195803.2:c.1364T>C
  • NP_000518.1:p.Leu582Pro
  • NP_000518.1:p.Leu582Pro
  • NP_001182727.1:p.Leu582Pro
  • NP_001182728.1:p.Leu541Pro
  • NP_001182729.1:p.Leu414Pro
  • NP_001182732.1:p.Leu455Pro
  • LRG_274t1:c.1745T>C
  • LRG_274:g.32518T>C
  • LRG_274p1:p.Leu582Pro
  • NC_000019.9:g.11227574T>C
  • NM_000527.4(LDLR):c.1745T>C
  • NM_000527.4:c.1745T>C
  • c.1745T>C
Protein change:
L414P
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000980; dbSNP: rs875989930
NCBI 1000 Genomes Browser:
rs875989930
Molecular consequence:
  • NM_000527.5:c.1745T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1745T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1622T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1241T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1364T>C - 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
SCV000909177Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Mar 22, 2019)
germlineclinical testing

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

SCV000957611Invitaecriteria provided, single submitter
Likely pathogenic
(Jan 23, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001422865Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedUncertain significance
(Jan 22, 2020)
germlinecuration

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Description

This missense variant (also known as p.Leu561Pro in the mature protein) is located in the fifth LDLR type B repeat 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 the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11668627, 15199436, 15576851, 17353666, 28161202, 27765764). 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.

SCV000909177

Summary from all submissions

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

Citations

PubMed

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]
PMID:
25741868
PMCID:
PMC4544753

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]
PMID:
27765764
See all PubMed Citations (6)

Details of each submission

From Color Health, Inc, SCV000909177.2

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

From Invitae, SCV000957611.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces leucine with proline at codon 582 of the LDLR protein (p.Leu582Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 11668627, 15199436, 27765764). This variant is also known as L561P in the literature. ClinVar contains an entry for this variant (Variation ID: 226372). 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. 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 Broad Institute Rare Disease Group, Broad Institute, SCV001422865.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

The p.Leu582Pro variant in LDLR has been reported in 4 European individuals with familial hypercholesterolemia (PMID: 28161202, 15199436, 11668627), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 226372). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015).

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

Last Updated: Dec 4, 2021

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