NM_000527.5(LDLR):c.345C>G (p.Arg115=) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Dec 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002470938.3

Allele description [Variation Report for NM_000527.5(LDLR):c.345C>G (p.Arg115=)]

NM_000527.5(LDLR):c.345C>G (p.Arg115=)

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.345C>G (p.Arg115=)

HGVS:

NC_000019.10:g.11105251C>G
NG_009060.1:g.20871C>G
NM_000527.5:c.345C>GMANE SELECT
NM_001195798.2:c.345C>G
NM_001195799.2:c.222C>G
NM_001195800.2:c.314-2141C>G
NM_001195803.2:c.314-1314C>G
NP_000518.1:p.Arg115=
NP_000518.1:p.Arg115=
NP_001182727.1:p.Arg115=
NP_001182728.1:p.Arg74=
LRG_274t1:c.345C>G
LRG_274:g.20871C>G
LRG_274p1:p.Arg115=
NC_000019.9:g.11215927C>G
NM_000527.4:c.345C>G

Links:

dbSNP: rs150144164

NCBI 1000 Genomes Browser:

rs150144164

Molecular consequence:

NM_001195800.2:c.314-2141C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1314C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.345C>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.345C>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.222C>G - synonymous variant - [Sequence Ontology: SO:0001819]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002769528	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Oct 19, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10978268, 25741868
SCV004820153	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002769528

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Oct 19, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004820153

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Dec 1, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	15	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]

PMID:: 10978268

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769528.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolemia 1 (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0107 - This gene is associated with autosomal dominant disease however compound heterozygotes and homozygotes have been reported (OMIM; PMID: 10978268). (I) 0200 - Variant is predicted to result in a synonymous change. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (25 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0600 - Variant is located in an annotated LDLa superfamily domain (NCBI, PDB). (I) 0705 - No comparable synonymous variants have previous evidence for pathogenicity. However, a different variant affecting the same nucleotide, c.345C>T (p.(Arg115=) has been reported by a research laboratory (ClinVar). (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. This variant has been reported as likely benign and benign in ClinVar. (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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, SCV004820153.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		15	not provided	not provided	not provided

Last Updated: Feb 25, 2025

ClinVar

Relating variation to medicine