NM_000527.5(LDLR):c.1060+10G>C AND not specified

Germline classification:: Benign (8 submissions)
Last evaluated:: Apr 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000213292.26

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

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

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>C

Other names:

HGVS:

NC_000019.10:g.11110781G>C
NG_009060.1:g.26401G>C
NM_000527.5:c.1060+10G>CMANE SELECT
NM_001195798.2:c.1060+10G>C
NM_001195799.2:c.937+10G>C
NM_001195800.2:c.556+10G>C
NM_001195803.2:c.679+10G>C
LRG_274t1:c.1060+10G>C
LRG_274:g.26401G>C
NC_000019.9:g.11221457G>C
NM_000527.3:c.1060+10G>C
NM_000527.4:c.1060+10G>C
NM_000527.4:c.1060+7_1060+10delinsCCCC
c.1060+10G>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000478;

Molecular consequence:

NM_000527.5:c.1060+10G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1060+10G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.937+10G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.556+10G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.679+10G>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000269221	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Mar 6, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000304679	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000517222	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Sep 30, 2016)	germline	clinical testing	Citation Link,
SCV000614002	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Benign (Aug 2, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001743196	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Benign	germline	clinical testing
SCV001922064	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001954536	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV003929049	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Apr 4, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000269221.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

c.1060+10G>C in intron 7 of LDLR: This variant is not expected to have clinical significance because it has been identified in 38.5% (46591/121050) of total chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs12710260).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	3	not provided

From PreventionGenetics, part of Exact Sciences, SCV000304679.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000517222.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000614002.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001743196.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001922064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954536.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929049.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: LDLR c.1060+7_1060+10delinsCCCC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. A constituent SNV, c.1060+10G>C of the variant allele was found at a frequency of 0.39 in 281296 control chromosomes in the gnomAD database (v2.1.1), including 23526 homozygotes. The other constituent SNV of this variant allele, c.1060+7T>C was found at a frequency of 0.9999 in control chromosomes in the gnomAD database (v2.1.1), and therefore, near complete overlap of the c.1060+10G>C occurrences can be assumed. The observed frequency of the c.1060+10G>C variant is approximately 311.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1060+7_1060+10delinsCCCC in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

Relating variation to medicine