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NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) AND Homozygous familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 7, 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:
RCV000844749.12

Allele description [Variation Report for NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)]

NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)

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.1414G>T (p.Asp472Tyr)
HGVS:
  • NC_000019.10:g.11113590G>T
  • NG_009060.1:g.29210G>T
  • NM_000527.5:c.1414G>TMANE SELECT
  • NM_001195798.2:c.1414G>T
  • NM_001195799.2:c.1291G>T
  • NM_001195800.2:c.910G>T
  • NM_001195803.2:c.1033G>T
  • NP_000518.1:p.Asp472Tyr
  • NP_000518.1:p.Asp472Tyr
  • NP_001182727.1:p.Asp472Tyr
  • NP_001182728.1:p.Asp431Tyr
  • NP_001182729.1:p.Asp304Tyr
  • NP_001182732.1:p.Asp345Tyr
  • LRG_274t1:c.1414G>T
  • LRG_274:g.29210G>T
  • LRG_274p1:p.Asp472Tyr
  • NC_000019.9:g.11224266G>T
  • NM_000527.4:c.1414G>T
  • NM_000527.5:c.1414G>T
  • c.1414G>T
  • p.(Asp472Tyr)
  • p.D472Y
Protein change:
D304Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000886; dbSNP: rs730882102
NCBI 1000 Genomes Browser:
rs730882102
Molecular consequence:
  • NM_000527.5:c.1414G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1414G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1291G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.910G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1033G>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536] - Comment(s)
Observations:
4

Condition(s)

Name:
Homozygous familial hypercholesterolemia
Synonyms:
Familial hypercholesterolemia - homozygous
Identifiers:
MONDO: MONDO:0018328; MedGen: C0342881

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000731720Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Apr 7, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown44not providednot providednot providedclinical testing

Citations

PubMed

Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening.

Campagna F, Martino F, Bifolco M, Montali A, Martino E, Morrone F, Antonini R, Cantafora A, Verna R, Arca M.

Atherosclerosis. 2008 Jan;196(1):356-364. doi: 10.1016/j.atherosclerosis.2006.11.015. Epub 2006 Dec 28.

PubMed [citation]
PMID:
17196209

The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2012 Aug;223(2):401-8. doi: 10.1016/j.atherosclerosis.2012.05.014. Epub 2012 May 23.

PubMed [citation]
PMID:
22698793
See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731720.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (9)

Description

The p.Asp472Tyr variant in LDLR (also described as p.Asp451Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and 12 individuals who had a myocardial infarction, and segregated with disease in 3 affected relatives from 2 families (Abul-Husn 2016 PMID: 28008010, Vohnout 2016 PMID: 27542166, Thormaehlen 2015 PMID: 25647241, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Campagna 2008 PMID: 17196209, ClinVar submission IDs: SCV000503344.1, SCV000540817.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183116) and has been identified in 0.02% (5/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, and in vitro functional assays were unclear in their overall impact (Thormaehlen 2015 PMID: 25647241). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided4not provided4not provided

Last Updated: Oct 13, 2024