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NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) AND Hypercholesterolemia, familial, 1

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 28, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000237163.2

Allele description [Variation Report for NM_000527.5(LDLR):c.760C>T (p.Gln254Ter)]

NM_000527.5(LDLR):c.760C>T (p.Gln254Ter)

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.760C>T (p.Gln254Ter)
Other names:
NM_000527.5(LDLR):c.760C>T; p.Gln254Ter
HGVS:
  • NC_000019.10:g.11106630C>T
  • NG_009060.1:g.22250C>T
  • NM_000527.5:c.760C>TMANE SELECT
  • NM_001195798.2:c.760C>T
  • NM_001195799.2:c.637C>T
  • NM_001195800.2:c.314-762C>T
  • NM_001195803.2:c.379C>T
  • NP_000518.1:p.Gln254Ter
  • NP_001182727.1:p.Gln254Ter
  • NP_001182728.1:p.Gln213Ter
  • NP_001182732.1:p.Gln127Ter
  • LRG_274:g.22250C>T
  • NC_000019.9:g.11217306C>T
  • c.760C>T
Protein change:
Q127*
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001836; dbSNP: rs759109699
NCBI 1000 Genomes Browser:
rs759109699
Molecular consequence:
  • NM_001195800.2:c.314-762C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.760C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001195798.2:c.760C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001195799.2:c.637C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001195803.2:c.379C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hypercholesterolemia, familial, 1
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000294954LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Pathogenic
(Mar 25, 2016) 		germlineliterature only

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

Citation Link,

SCV002568017ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)		Pathogenic
(Aug 28, 2022) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]
PMID:
23375686

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294954.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002568017.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493). -- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met. PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China, so PP4 is met.

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

Last Updated: Aug 5, 2023