NM_000527.5(LDLR):c.367T>C (p.Ser123Pro) AND Familial hypercholesterolemia

Clinical significance:Uncertain significance (Last evaluated: Dec 1, 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:
RCV001042933.2

Allele description [Variation Report for NM_000527.5(LDLR):c.367T>C (p.Ser123Pro)]

NM_000527.5(LDLR):c.367T>C (p.Ser123Pro)

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.367T>C (p.Ser123Pro)
HGVS:
  • NC_000019.10:g.11105273T>C
  • NG_009060.1:g.20893T>C
  • NM_000527.5:c.367T>CMANE SELECT
  • NM_001195798.2:c.367T>C
  • NM_001195799.2:c.244T>C
  • NM_001195800.2:c.314-2119T>C
  • NM_001195803.2:c.314-1292T>C
  • NP_000518.1:p.Ser123Pro
  • NP_000518.1:p.Ser123Pro
  • NP_001182727.1:p.Ser123Pro
  • NP_001182728.1:p.Ser82Pro
  • LRG_274t1:c.367T>C
  • LRG_274:g.20893T>C
  • LRG_274p1:p.Ser123Pro
  • NC_000019.9:g.11215949T>C
  • NM_000527.4:c.367T>C
  • c.367T>C
  • p.(Ser123Pro)
Protein change:
S123P
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001226; dbSNP: rs879254495
NCBI 1000 Genomes Browser:
rs879254495
Molecular consequence:
  • NM_001195800.2:c.314-2119T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1292T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.244T>C - 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
SCV001206642Invitaecriteria provided, single submitter
Uncertain significance
(Jan 16, 2019)
germlineclinical testing

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

SCV001353457Color Health, Inccriteria provided, single submitter
Uncertain significance
(Dec 1, 2019)
germlineclinical testing

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

Description

This missense variant (also known as p.Ser102Pro in the mature protein) replaces serine with proline at codon 123 of the LDLR protein. This variant occurs at a poorly conserved position of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 19446849, 20045108). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype (PMID: 20045108). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV001353457

Summary from all submissions

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

Citations

PubMed

The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia.

Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, Bertolini S.

J Pediatr. 2009 Aug;155(2):199-204.e2. doi: 10.1016/j.jpeds.2009.02.022. Epub 2009 May 15.

PubMed [citation]
PMID:
19446849

An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations.

Romano M, Di Taranto MD, Mirabelli P, D'Agostino MN, Iannuzzi A, Marotta G, Gentile M, Raia M, Di Noto R, Del Vecchio L, Rubba P, Fortunato G.

J Lipid Res. 2011 Nov;52(11):2095-100. doi: 10.1194/jlr.D017772. Epub 2011 Aug 24.

PubMed [citation]
PMID:
21865347
PMCID:
PMC3196240
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001206642.1

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

Description

This sequence change replaces serine with proline at codon 123 of the LDLR protein (p.Ser123Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with familial hypercholesterolemia (PMID: 19446849) and has been reported in combination with another LDLR variant, p.Ser493CysfsX42, in an individual with this disease (PMID: 20045108, 21865347). ClinVar contains an entry for this variant (Variation ID: 251181). 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 tolerated, but 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

From Color Health, Inc, SCV001353457.1

#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: Dec 4, 2021

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