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NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Apr 22, 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:
RCV000238279.5

Allele description [Variation Report for NM_000527.5(LDLR):c.758G>C (p.Arg253Pro)]

NM_000527.5(LDLR):c.758G>C (p.Arg253Pro)

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.758G>C (p.Arg253Pro)
Other names:
NM_000527.5(LDLR):c.758G>C; p.Arg253Pro
HGVS:
  • NC_000019.10:g.11106628G>C
  • NG_009060.1:g.22248G>C
  • NM_000527.5:c.758G>CMANE SELECT
  • NM_001195798.2:c.758G>C
  • NM_001195799.2:c.635G>C
  • NM_001195800.2:c.314-764G>C
  • NM_001195803.2:c.377G>C
  • NP_000518.1:p.Arg253Pro
  • NP_001182727.1:p.Arg253Pro
  • NP_001182728.1:p.Arg212Pro
  • NP_001182732.1:p.Arg126Pro
  • LRG_274:g.22248G>C
  • NC_000019.9:g.11217304G>C
  • c.758G>C
Protein change:
R126P
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000112; dbSNP: rs139507589
NCBI 1000 Genomes Browser:
rs139507589
Molecular consequence:
  • NM_001195800.2:c.314-764G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.758G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.758G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.635G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.377G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000294953LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Likely pathogenic
(Mar 25, 2016) 		germlineliterature only

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

Citation Link,

SCV002506380ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)		Uncertain significance
(Apr 22, 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

Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.

Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, Neely RD, Fairgrieve S, Nair D, Barbir M, Jones JL, Egan S, Everdale R, Lolin Y, Hughes E, Cooper JA, Hadfield SG, Norbury G, Humphries SE.

Clin Genet. 2010 Jun;77(6):572-80. doi: 10.1111/j.1399-0004.2009.01356.x. Epub 2010 Mar 13.

PubMed [citation]
PMID:
20236128

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294953.2

#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, SCV002506380.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID: 20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable).

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

Last Updated: Jun 23, 2024