NM_000527.5(LDLR):c.1060+10G>A AND Familial hypercholesterolemia 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Likely pathogenic(1);Pathogenic(1);Uncertain significance(3) (Last evaluated: May 24, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000238168.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1060+10G>A]

NM_000527.5(LDLR):c.1060+10G>A

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.1060+10G>A
HGVS:
  • NC_000019.10:g.11110781G>A
  • NG_009060.1:g.26401G>A
  • NM_000527.5:c.1060+10G>AMANE SELECT
  • NM_001195798.2:c.1060+10G>A
  • NM_001195799.2:c.937+10G>A
  • NM_001195800.2:c.556+10G>A
  • NM_001195803.2:c.679+10G>A
  • LRG_274t1:c.1060+10G>A
  • LRG_274:g.26401G>A
  • NC_000019.9:g.11221457G>A
  • NM_000527.4(LDLR):c.1060+10G>A
  • NM_000527.4:c.1060+10G>A
  • c.1060+10G>A
  • p.(Asp354Glyfs*20)
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000880;
Molecular consequence:
  • NM_000527.5:c.1060+10G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195798.2:c.1060+10G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195799.2:c.937+10G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195800.2:c.556+10G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.679+10G>A - intron variant - [Sequence Ontology: SO:0001627]
Observations:
10

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
SCV000295175LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely benign
(Mar 25, 2016)
germlineliterature only

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

Citation Link,

SCV000503290Centre 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
Likely pathogenic
(Dec 16, 2016)
germlineclinical testing

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

SCV000588547Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasilcriteria provided, single submitter
Uncertain significance
(Mar 1, 2016)
germlineresearch

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

SCV000607553Fundacion Hipercolesterolemia Familiar - SAFEHEARTcriteria provided, single submitter
Uncertain significance
(Mar 1, 2016)
germlineresearch

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

SCV000782906Robarts Research Institute,Western Universitycriteria provided, single submitter
Uncertain significance
(Jan 2, 2018)
germlineclinical testing

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

SCV001422917Broad 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,

SCV001653618Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico IIcriteria provided, single submitter
Pathogenic
(May 24, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation
not providedgermlineyes9not providednot provided2603not providedclinical testing, literature only
Caucasiangermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.

Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O.

Atherosclerosis. 2005 May;180(1):155-60. Epub 2005 Jan 12.

PubMed [citation]
PMID:
15823288

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]
PMID:
23375686
See all PubMed Citations (6)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295175.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (3)
2not provided1not providednot providedliterature only PubMed (3)
3not provided1not providednot providedliterature only PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not 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, SCV000503290.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testing PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 6 , family member = 1

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided6not providednot providednot provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588547.1

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

Description

%MAF(ExAC):0.0008261

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

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607553.1

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

Description

%MAF(ExAC):0.0008261

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

From Robarts Research Institute,Western University, SCV000782906.1

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

From Broad Institute Rare Disease Group, Broad Institute, SCV001422917.1

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

Description

The c.1060+10G>A variant in LDLR has been reported in 6 individuals (including 3 French and 2 Italian individuals) with Familial Hypercholesterolemia, segregated with disease in 2 affected relatives from 1 family (PMID: 12436241, 23375686, 28965616), and has been identified in 0.01088% (2/18376) of East Asian chromosomes and 0.003267% (1/30608) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12710260). This variant has also been reported as a VUS, a likely benign variant, and a likely pathogenic variant in ClinVar (Variation ID: 251625). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the c.1060+10G>A variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting (Richards 2015).

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

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653618.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian1not providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Nov 27, 2021

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