VCV000251012.29 - ClinVar

NM_000527.5(LDLR):c.90C>T (p.Asn30=)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(6); Likely benign(3)

10 out of 13 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.90C>T (p.Asn30=)

Variation ID: 251012 Accession: VCV000251012.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11100245 (GRCh38) [ NCBI UCSC ] 19: 11210921 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 29, 2016	Feb 16, 2025	Feb 2, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.90C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Asn30=	synonymous
NM_001195798.2:c.90C>T	NP_001182727.1:p.Asn30=	synonymous
NM_001195799.2:c.90C>T	NP_001182728.1:p.Asn30=	synonymous
NM_001195800.2:c.90C>T	NP_001182729.1:p.Asn30=	synonymous
NM_001195803.2:c.90C>T	NP_001182732.1:p.Asn30=	synonymous
NC_000019.10:g.11100245C>T
NC_000019.9:g.11210921C>T
NG_009060.1:g.15865C>T
LRG_274:g.15865C>T
LRG_274t1:c.90C>T	LRG_274p1:p.Asn30=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:11100244:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.01158 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00227

Exome Aggregation Consortium (ExAC) 0.00293

Trans-Omics for Precision Medicine (TOPMed) 0.00954

The Genome Aggregation Database (gnomAD) 0.00965

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01092

1000 Genomes Project 0.01158

1000 Genomes Project 30x 0.01171

Links

ClinGen: CA041739 LDLR-LOVD, British Heart Foundation: LDLR_001196 dbSNP: rs72658855 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LDLR		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4225	4527

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypercholesterolemia, familial, 1	Conflicting classifications of pathogenicity (6)	criteria provided, conflicting classifications	Jan 13, 2018	RCV000237404.17
not provided	Benign (1)	criteria provided, single submitter	Nov 23, 2022	RCV000759077.6
not specified	Benign (1)	criteria provided, single submitter	Jan 9, 2017	RCV000440331.1
Familial hypercholesterolemia	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 2, 2025	RCV001081718.13
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jan 9, 2015	RCV002446469.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Mar 25, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia Affected status: yes, no Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000294458.2 First in ClinVar: Jul 29, 2016 Last updated: May 26, 2018	Publications: PubMed (2) PubMed: 12052488‚ 25606447 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Uncertain significance (Mar 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000322876.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Comment: 0/190 non-FH alleles Observation 1: Comment on evidence: %MAF (ExAC):0.2932 Observation 2:
Benign (Jan 09, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000528018.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Jan 02, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000782954.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Likely benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000410525.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jul 06, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000689782.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Nov 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888169.3 First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 25606447‚ 12052488
Likely benign (Jan 09, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002682875.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Feb 02, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000556787.9 First in ClinVar: Dec 06, 2016 Last updated: Feb 16, 2025
Benign (Nov 09, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Chora et al. (Genet Med. 2022)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005074012.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606011.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Likely benign (Nov 15, 2019) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002086357.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Likely benign (Feb 09, 2023) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003836770.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Familial hypercholesterolemia: Molecular characterization of possible cases from the Azores Islands (Portugal).	Cymbron T	Meta gene	2014	PMID: 25606447
Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene.	Lind S	Atherosclerosis	2002	PMID: 12052488

Text-mined citations for rs72658855 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.90C>T (p.Asn30=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72658855 ...