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NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Jul 2, 2024
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:
RCV000238205.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1928C>T (p.Ala643Val)]

NM_000527.5(LDLR):c.1928C>T (p.Ala643Val)

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.1928C>T (p.Ala643Val)
Other names:
NM_000527.5(LDLR):c.1928C>T
HGVS:
  • NC_000019.10:g.11120174C>T
  • NG_009060.1:g.35794C>T
  • NM_000527.5:c.1928C>TMANE SELECT
  • NM_001195798.2:c.1928C>T
  • NM_001195799.2:c.1805C>T
  • NM_001195800.2:c.1424C>T
  • NM_001195803.2:c.1547C>T
  • NP_000518.1:p.Ala643Val
  • NP_000518.1:p.Ala643Val
  • NP_001182727.1:p.Ala643Val
  • NP_001182728.1:p.Ala602Val
  • NP_001182729.1:p.Ala475Val
  • NP_001182732.1:p.Ala516Val
  • LRG_274t1:c.1928C>T
  • LRG_274:g.35794C>T
  • LRG_274p1:p.Ala643Val
  • NC_000019.9:g.11230850C>T
  • NM_000527.4:c.1928C>T
  • c.1928C>T
Protein change:
A475V
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001552; dbSNP: rs879255075
NCBI 1000 Genomes Browser:
rs879255075
Molecular consequence:
  • NM_000527.5:c.1928C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1928C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1805C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1424C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1547C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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
SCV000295757LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

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

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

Citation Link,

SCV000503433Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Dec 16, 2016) 		germlineclinical testing

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

SCV005328529ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)		Uncertain Significance
(Jul 2, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot provided2601not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]
PMID:
20809525
PMCID:
PMC3152176

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 LDLR-LOVD, British Heart Foundation, SCV000295757.2

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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503433.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

subject mutated among 2600 FH index cases screened = 1/software prediction damaging

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided1not providednot providednot provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005328529.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). BP4: REVEL = 0.481; score is below 0.50, splicing evaluation required. A). Not on limits. B). it creates a GT. Variant is exonic and at least 50bp upstream/downstream from canonical donor/acceptor site and creates a de novo GT. MES scores: variant cryptic site = -9.79, WT cryptic site = -17.54, canonical donor site= 10.28. De novo score is negative, so it is not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon-Broome criteria for FH (PMID 20809525) after alternative causes of high cholesterol were excluded.

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

Last Updated: Oct 8, 2024