NM_000527.5(LDLR):c.1837G>A (p.Val613Ile) AND Familial hypercholesterolemia

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Oct 2, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000771315.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1837G>A (p.Val613Ile)]

NM_000527.5(LDLR):c.1837G>A (p.Val613Ile)

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.1837G>A (p.Val613Ile)
HGVS:
  • NC_000019.10:g.11116990G>A
  • NG_009060.1:g.32610G>A
  • NM_000527.4:c.1837G>A
  • NM_000527.5:c.1837G>AMANE SELECT
  • NM_001195798.2:c.1837G>A
  • NM_001195799.2:c.1714G>A
  • NM_001195800.2:c.1333G>A
  • NM_001195803.2:c.1456G>A
  • NP_000518.1:p.Val613Ile
  • NP_000518.1:p.Val613Ile
  • NP_001182727.1:p.Val613Ile
  • NP_001182728.1:p.Val572Ile
  • NP_001182729.1:p.Val445Ile
  • NP_001182732.1:p.Val486Ile
  • LRG_274t1:c.1837G>A
  • LRG_274:g.32610G>A
  • LRG_274p1:p.Val613Ile
  • NC_000019.9:g.11227666G>A
  • c.1837G>A
Protein change:
V445I
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000250;
Molecular consequence:
  • NM_000527.4:c.1837G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1837G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1837G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1714G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1333G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1456G>A - 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
SCV000903571Color Health, Inccriteria provided, single submitter
Likely benign
(Mar 14, 2018)
germlineclinical testing

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

SCV000945773Invitaecriteria provided, single submitter
Uncertain significance
(Oct 2, 2018)
germlineclinical testing

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

Summary from all submissions

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

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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]
PMID:
16250003
See all PubMed Citations (4)

Details of each submission

From Color Health, Inc, SCV000903571.1

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

From Invitae, SCV000945773.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces valine with isoleucine at codon 613 of the LDLR protein (p.Val613Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs148181903, ExAC 0.01%). This variant has been observed in individuals affected with hypercholesterolemia (PMID: 16250003, 19837725). ClinVar contains an entry for this variant (Variation ID: 161288). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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