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NM_000527.5(LDLR):c.971G>T (p.Gly324Val) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 30, 2023
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:
RCV003994664.1

Allele description [Variation Report for NM_000527.5(LDLR):c.971G>T (p.Gly324Val)]

NM_000527.5(LDLR):c.971G>T (p.Gly324Val)

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.971G>T (p.Gly324Val)
HGVS:
  • NC_000019.10:g.11110682G>T
  • NG_009060.1:g.26302G>T
  • NM_000527.5:c.971G>TMANE SELECT
  • NM_001195798.2:c.971G>T
  • NM_001195799.2:c.848G>T
  • NM_001195800.2:c.467G>T
  • NM_001195803.2:c.590G>T
  • NP_000518.1:p.Gly324Val
  • NP_000518.1:p.Gly324Val
  • NP_001182727.1:p.Gly324Val
  • NP_001182728.1:p.Gly283Val
  • NP_001182729.1:p.Gly156Val
  • NP_001182732.1:p.Gly197Val
  • LRG_274t1:c.971G>T
  • LRG_274:g.26302G>T
  • LRG_274p1:p.Gly324Val
  • NC_000019.9:g.11221358G>T
  • NM_000527.4:c.971G>T
Protein change:
G156V
Molecular consequence:
  • NM_000527.5:c.971G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.971G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.848G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.467G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.590G>T - 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
SCV004812501Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 30, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812501.1

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

Description

This sequence change in LDLR is predicted to replace glycine with valine at codon 324, p.(Gly324Val). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the EGF-like 1 domain. There is a large physicochemical difference between glycine and valine. This variant is absent from the population database gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the relevant literature. At least one patient with this variant displayed a clinical diagnosis of familial hypercholesterolaemia (FH) with a Dutch Lipid Clinic Network score of 6, which is highly specific for FH (Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3, PP4.

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

Last Updated: Apr 20, 2024