VCV000251836.21 - ClinVar

NM_000527.5(LDLR):c.1424C>T (p.Ala475Val)

Germline

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.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.1424C>T (p.Ala475Val)

Variation ID: 251836 Accession: VCV000251836.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11113600 (GRCh38) [ NCBI UCSC ] 19: 11224276 (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	May 1, 2024	Feb 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1424C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Ala475Val	missense
NM_001195798.2:c.1424C>T	NP_001182727.1:p.Ala475Val	missense
NM_001195799.2:c.1301C>T	NP_001182728.1:p.Ala434Val	missense
NM_001195800.2:c.920C>T	NP_001182729.1:p.Ala307Val	missense
NM_001195803.2:c.1043C>T	NP_001182732.1:p.Ala348Val	missense
NC_000019.10:g.11113600C>T
NC_000019.9:g.11224276C>T
NG_009060.1:g.29220C>T
LRG_274:g.29220C>T
LRG_274t1:c.1424C>T

... more HGVS ... less HGVS

Protein change

A475V, A434V, A307V, A348V

Other names

Canonical SPDI

NC_000019.10:11113599: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.

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

Links

ClinGen: CA10585447 LDLR-LOVD, British Heart Foundation: LDLR_001426 dbSNP: rs879254897 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	4075	4351

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	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 16, 2016	RCV000238538.10
Familial hypercholesterolemia	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Oct 17, 2023	RCV001248906.12
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Feb 7, 2024	RCV004020966.1

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.
Likely pathogenic (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000295423.2 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Publications: PubMed (1) PubMed: 20809525 Number of individuals with the variant: 1
Likely pathogenic (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503347.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Comment: subjects mutated among 2600 FH index cases screened = 2/Software predictions: Conflicting Number of individuals with the variant: 2
Uncertain significance (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001422599.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022	Publications: PubMed (1) PubMed: 20809525 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f115b998-6cb6-42f1-a3d4-3788f655a627 Comment: The p.Ala475Val variant in LDLR has been reported in 2 French individuals with familial hypercholesterolemia (PMID: 20809525), and was absent from large population studies. This … (more) The p.Ala475Val variant in LDLR has been reported in 2 French individuals with familial hypercholesterolemia (PMID: 20809525), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 251836). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015). (less)
Likely pathogenic (Oct 17, 2023)	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: SCV004376691.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 20809525 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 475 of the LDLR protein (p.Ala475Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 475 of the LDLR protein (p.Ala475Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 20809525). ClinVar contains an entry for this variant (Variation ID: 251836). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Feb 07, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005035976.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 20809525 Comment: The p.A475V variant (also known as c.1424C>T), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide … (more) The p.A475V variant (also known as c.1424C>T), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1424. The alanine at codon 475 is replaced by valine, an amino acid with similar properties. This variant has been detected in two probands from a familial hypercholesterolemia cohort (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
Likely pathogenic (Jul 21, 2023)	no assertion criteria provided Method: research	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	deCODE genetics, Amgen Accession: SCV004022247.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: The variant NM_000527.5:c.1424C>T (chr19:11113600) in LDLR was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar … (more) The variant NM_000527.5:c.1424C>T (chr19:11113600) in LDLR was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PM1, PM2, PP3, PP5) this variant classifies as likely pathogenic. (less) Number of individuals with the variant: 1 Ethnicity/Population group: Icelandic

Comment:

The p.Ala475Val variant in LDLR has been reported in 2 French individuals with familial hypercholesterolemia (PMID: 20809525), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 251836). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015).

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 475 of the LDLR protein (p.Ala475Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 20809525). ClinVar contains an entry for this variant (Variation ID: 251836). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The p.A475V variant (also known as c.1424C>T), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1424. The alanine at codon 475 is replaced by valine, an amino acid with similar properties. This variant has been detected in two probands from a familial hypercholesterolemia cohort (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

Comment:

The variant NM_000527.5:c.1424C>T (chr19:11113600) in LDLR was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PM1, PM2, PP3, PP5) this variant classifies as likely pathogenic.

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
Molecular spectrum of autosomal dominant hypercholesterolemia in France.	Marduel M	Human mutation	2010	PMID: 20809525
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f115b998-6cb6-42f1-a3d4-3788f655a627	-	-	-	-

Text-mined citations for rs879254897 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.1424C>T (p.Ala475Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs879254897 ...