NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) AND Familial hypercholesterolemia 1

Clinical significance:Likely pathogenic (Last evaluated: Jun 18, 2021)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000237217.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)]

NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)

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.1855T>C (p.Phe619Leu)
Other names:
NP_000518.1:p.F619L; NM_000527.5(LDLR):c.1855T>C
HGVS:
  • NC_000019.10:g.11120101T>C
  • NG_009060.1:g.35721T>C
  • NM_000527.5:c.1855T>CMANE SELECT
  • NM_001195798.2:c.1855T>C
  • NM_001195799.2:c.1732T>C
  • NM_001195800.2:c.1351T>C
  • NM_001195803.2:c.1474T>C
  • NP_000518.1:p.Phe619Leu
  • NP_000518.1:p.Phe619Leu
  • NP_001182727.1:p.Phe619Leu
  • NP_001182728.1:p.Phe578Leu
  • NP_001182729.1:p.Phe451Leu
  • NP_001182732.1:p.Phe492Leu
  • LRG_274t1:c.1855T>C
  • LRG_274:g.35721T>C
  • LRG_274p1:p.Phe619Leu
  • NC_000019.9:g.11230777T>C
  • NM_000527.4:c.1855T>C
  • c.1855T>C
Protein change:
F451L
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000570; dbSNP: rs747134711
NCBI 1000 Genomes Browser:
rs747134711
Molecular consequence:
  • NM_000527.5:c.1855T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1855T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1732T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1474T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Name:
Familial hypercholesterolemia 1 (FHCL1)
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
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)
OriginMethodCitations
SCV000295715LDLR-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,

SCV000484688Robarts Research Institute,Western Universitycriteria provided, single submitter
Uncertain significance
(Aug 22, 2019)
germlineclinical testing

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

SCV000503426Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foixcriteria provided, single submitter
Uncertain significance
(Dec 16, 2016)
germlineclinical testing

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

SCV000606541Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrumno assertion criteria providedPathogenicgermlineresearch

SCV001960933ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGenreviewed by expert panel
Likely pathogenic
(Jun 18, 2021)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes3not providednot provided2601not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation

Citations

PubMed

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

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
See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295715.2

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

From Robarts Research Institute,Western University, SCV000484688.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503426.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

subject mutated among 2600 FH index cases screened = 1 / Other mutation at same codon/Software predictions: Conflicting

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided1not providednot providednot provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, SCV000606541.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGen, SCV001960933.1

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

Description

NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00003266 (0.003266%) in East Asian (gnomAD v2.1.1). PP3 - REVEL: 0,857. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling validated clinical criteria for FH from different labs. PS3_supporting - PMID: 9409298 - Level 3 assay - study on htz patient's cultured lymphoblasts, immunoblotting + I125-LDL assay, no precursor detectable, degradation of 125I-LDL 63%. ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)).

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

Last Updated: Dec 4, 2021

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