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NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 13, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002327173.2

Allele description [Variation Report for NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)]

NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)

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.440C>T (p.Thr147Ile)
Other names:
NM_000527.5(LDLR):c.440C>T; p.Thr147Ile
HGVS:
  • NC_000019.10:g.11105346C>T
  • NG_009060.1:g.20966C>T
  • NM_000527.5:c.440C>TMANE SELECT
  • NM_001195798.2:c.440C>T
  • NM_001195799.2:c.317C>T
  • NM_001195800.2:c.314-2046C>T
  • NM_001195803.2:c.314-1219C>T
  • NP_000518.1:p.Thr147Ile
  • NP_000518.1:p.Thr147Ile
  • NP_001182727.1:p.Thr147Ile
  • NP_001182728.1:p.Thr106Ile
  • LRG_274t1:c.440C>T
  • LRG_274:g.20966C>T
  • LRG_274p1:p.Thr147Ile
  • NC_000019.9:g.11216022C>T
  • NM_000527.4:c.440C>T
  • c.440C>T
  • p.(Thr147Ile)
Protein change:
T106I
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000314; dbSNP: rs879254524
NCBI 1000 Genomes Browser:
rs879254524
Molecular consequence:
  • NM_001195800.2:c.314-2046C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1219C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.440C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.440C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.317C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002633357Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Sep 13, 2021) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

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

Details of each submission

From Ambry Genetics, SCV002633357.2

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

Description

The p.T147I variant (also known as c.440C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 440. The threonine at codon 147 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in two individuals from a familial hypercholesterolemia cohort and shown to reduce LDLR activity to 56% of normal levels in vivo (Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Jan 13, 2025