NM_000527.5(LDLR):c.2026G>A (p.Gly676Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Oct 2, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000237787.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2026G>A (p.Gly676Ser)]

NM_000527.5(LDLR):c.2026G>A (p.Gly676Ser)

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.2026G>A (p.Gly676Ser)

HGVS:

NC_000019.10:g.11120408G>A
NG_009060.1:g.36028G>A
NM_000527.5:c.2026G>AMANE SELECT
NM_001195798.2:c.2026G>A
NM_001195799.2:c.1903G>A
NM_001195800.2:c.1522G>A
NM_001195803.2:c.1606+175G>A
NP_000518.1:p.Gly676Ser
NP_000518.1:p.Gly676Ser
NP_001182727.1:p.Gly676Ser
NP_001182728.1:p.Gly635Ser
NP_001182729.1:p.Gly508Ser
LRG_274t1:c.2026G>A
LRG_274:g.36028G>A
LRG_274p1:p.Gly676Ser
NC_000019.9:g.11231084G>A
NM_000527.4:c.2026G>A
c.2026G>A

Protein change:

G508S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000946; dbSNP: rs745753810

NCBI 1000 Genomes Browser:

rs745753810

Molecular consequence:

NM_001195803.2:c.1606+175G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2026G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2026G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1903G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1522G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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uncharacterized protein C2orf66 homolog [Canis lupus familiaris]
uncharacterized protein C2orf66 homolog [Canis lupus familiaris]
gi|1953375942|ref|XP_038303264.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295822	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000606575	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607666	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004818483	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12417285, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H.

Atherosclerosis. 2002 Dec;165(2):335-42. Erratum in: Atherosclerosis. 2004 Jun;174(2):399-400.

PubMed [citation]

PMID:: 12417285

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, SCV000295822.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607666.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

%MAF(ExAC):0.00166

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004818483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant (also known as p.Gly655Ser in the mature protein) replaces glycine with serine at codon 676 of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 12417285). This variant has also been identified in 3/250686 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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