NM_000527.4(LDLR):c.1067A>T (p.Asp356Val) AND Familial hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Sep 16, 2019)

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:
RCV001187845.2

Allele description [Variation Report for NM_000527.4(LDLR):c.1067A>T (p.Asp356Val)]

NM_000527.4(LDLR):c.1067A>T (p.Asp356Val)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.4(LDLR):c.1067A>T (p.Asp356Val)
HGVS:
  • NC_000019.10:g.11111520A>T
  • NG_009060.1:g.27140A>T
  • NM_000527.4:c.1067A>T
  • NM_001195798.2:c.1067A>T
  • NM_001195799.2:c.944A>T
  • NM_001195800.2:c.563A>T
  • NM_001195803.2:c.686A>T
  • NP_000518.1:p.Asp356Val
  • NP_001182727.1:p.Asp356Val
  • NP_001182728.1:p.Asp315Val
  • NP_001182729.1:p.Asp188Val
  • NP_001182732.1:p.Asp229Val
  • LRG_274t1:c.1067A>T
  • LRG_274:g.27140A>T
  • LRG_274p1:p.Asp356Val
  • NC_000019.9:g.11222196A>T
Protein change:
D188V
Links:
dbSNP: rs879254777
NCBI 1000 Genomes Browser:
rs879254777
Molecular consequence:
  • NM_000527.4:c.1067A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1067A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.944A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.563A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.686A>T - 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
SCV001354737Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Jan 17, 2019)
germlineclinical testing

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

SCV001385849Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 16, 2019)
germlineclinical testing

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

Description

This missense variant (also known as p.Asp335Val in the mature protein) is located in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in an individual affected with familial hypercholesterolemia (Color Genomics internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Three, rare missense variants occurring at the same codon (p.Asp356His, p.Asp356Tyr, p.Asp356Ala) have been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9104431, 11851376, 15256764, 19319977, 20145306, 20809525), suggesting that p.Asp356 residue is important for the LDLR protein function. Based on available evidence, this variant is classified as Likely Pathogenic.

SCV001354737

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

A Japanese case of familial hypercholesterolemia with a novel mutation in the LDLR gene.

Nagahara K, Hachiya R, Tada H, Okada H, Yamagishi M, Dobashi K, Mizuno K, Hasegawa Y.

Clin Pediatr Endocrinol. 2019;28(1):19-22. doi: 10.1297/cpe.28.19. Epub 2019 Jan 31. No abstract available.

PubMed [citation]
PMID:
30745730
PMCID:
PMC6356093
See all PubMed Citations (5)

Details of each submission

From Color Health, Inc, SCV001354737.1

#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, SCV001385849.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces aspartic acid with valine at codon 356 of the LDLR protein (p.Asp356Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of familial hypercholesterolemia (PMID: 30745730, Invitae). ClinVar contains an entry for this variant (Variation ID: 440623). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp356 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 15998910). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: May 10, 2021

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