NM_000527.5(LDLR):c.1216C>A (p.Arg406=) AND Familial hypercholesterolemia

Clinical significance:Pathogenic (Last evaluated: Mar 19, 2018)

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:
RCV000588218.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1216C>A (p.Arg406=)]

NM_000527.5(LDLR):c.1216C>A (p.Arg406=)

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.1216C>A (p.Arg406=)
Other names:
R385R; NP_000518.1:p.Arg406Arg=
HGVS:
  • NC_000019.10:g.11113307C>A
  • NG_009060.1:g.28927C>A
  • NM_000527.4:c.1216C>A
  • NM_000527.5:c.1216C>AMANE SELECT
  • NM_001195798.2:c.1216C>A
  • NM_001195799.2:c.1093C>A
  • NM_001195800.2:c.712C>A
  • NM_001195803.2:c.835C>A
  • NP_000518.1:p.Arg406=
  • NP_000518.1:p.Arg406=
  • NP_001182727.1:p.Arg406=
  • NP_001182728.1:p.Arg365=
  • NP_001182729.1:p.Arg238=
  • NP_001182732.1:p.Arg279=
  • LRG_274t1:c.1216C>A
  • LRG_274:g.28927C>A
  • LRG_274p1:p.Arg406=
  • NC_000019.9:g.11223983C>A
  • c.1216C>A
Protein change:
ARG385ARG
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000813; OMIM: 606945.0065; dbSNP: rs121908043
NCBI 1000 Genomes Browser:
rs121908043
Molecular consequence:
  • NM_000527.4:c.1216C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_000527.5:c.1216C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195798.2:c.1216C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195799.2:c.1093C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195800.2:c.712C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195803.2:c.835C>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000697190Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jul 10, 2017)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001349490Color Health, Inccriteria provided, single submitter
Pathogenic
(Mar 19, 2018)
germlineclinical testing

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

Description

This variant changes a single nucleotide in exon 9 (c.1216C>A) of the LDLR gene and has been shown to create a new splice acceptor site. RNA studies in cells from familial hypercholesterolemia subjects have shown that the usage of the newly created splice acceptor causes a deletion of 31 nucleotides from the beginning of exon 9 of the LDLR gene, leading to frameshift and premature truncation of the mutant allele (PMID: 17335829, 18400033). As a result, normal transcript is not produced from the mutant allele. This variant has been identified in multiple individuals diagnosed with familial hypercholesterolemia, mostly of Chinese origin (PMID: 17335829, 18400033, 21382890, 28028493, 28235710). This variant has been identified in 1/245992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variant at the same position (c.1216C>T) is also shown to cause splice defect (PMID: 28169869). Based on available evidence, this variant is classified as Pathogenic.

SCV001349490

Summary from all submissions

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

Citations

PubMed

Functional analysis of the synonymous R385R mutation in the low-density lipoprotein receptor gene.

Tveten K, Khoo KL, Berge KE, Leren TP, Kulseth MA.

Genet Test Mol Biomarkers. 2009 Apr;13(2):243-8. doi: 10.1089/gtmb.2008.0125.

PubMed [citation]
PMID:
19371225

Mutation detection in Chinese patients with familial hypercholesterolemia.

Du R, Fan LL, Lin MJ, He ZJ, Huang H, Chen YQ, Li JJ, Xia K, Zhao SP, Xiang R.

Springerplus. 2016;5(1):2095. doi: 10.1186/s40064-016-3763-3.

PubMed [citation]
PMID:
28028493
PMCID:
PMC5153400
See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697190.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: The LDLR c.1216C>A (p.Arg406Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing by the introduction of a cryptic splice site and ESE finder predicts that this variant may affect ESE sites at the locus. In support of these predictions, functional studies have shown that the variant splice site is used preferentially over the wild type splice site in patient cell lines and in vitro splicing assays (Tveten_Genet Test Molec Biomarkers_2009; Bourbon_Ather_2007). Additionally, the variant has been cited in numerous patients with hypercholesterolemia and segregates with disease in families (e.g., van der Graaf_Circ_2011; Du_SpringerPlus_2016; Tveten_Genet Test Molec Biomarkers_2009). This variant is absent from the large control database ExAC and control cohorts from the literature (0/120510 control chromosomes). In addition, two reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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

From Color Health, Inc, SCV001349490.1

#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: Jun 14, 2021

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