VCV000375840.12 - ClinVar

NM_000527.5(LDLR):c.2479G>T (p.Val827Phe)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Uncertain significance

for Hypercholesterolemia, familial, 1

Classification is based on the expert panel submission

Jan 2022 by ClinGen Familial Hypercholesterolemia Variant Curation Expe…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.2479G>T (p.Val827Phe)

Variation ID: 375840 Accession: VCV000375840.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11129602 (GRCh38) [ NCBI UCSC ] 19: 11240278 (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	Mar 8, 2017	Feb 15, 2026	Jan 28, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2479G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Val827Phe	missense
NM_000527.4(LDLR):c.2479G>T
NM_001195798.2:c.2479G>T	NP_001182727.1:p.Val827Phe	missense
NM_001195799.2:c.2356G>T	NP_001182728.1:p.Val786Phe	missense
NM_001195800.2:c.1975G>T	NP_001182729.1:p.Val659Phe	missense
NM_001195803.2:c.1945G>T	NP_001182732.1:p.Val649Phe	missense
NC_000019.10:g.11129602G>T
NC_000019.9:g.11240278G>T
NG_009060.1:g.45222G>T
LRG_274:g.45222G>T
LRG_274t1:c.2479G>T	LRG_274p1:p.Val827Phe

... more HGVS ... less HGVS

Protein change

V827F, V659F, V786F, V649F

Other names

NM_000527.5(LDLR):c.2479G>T

Canonical SPDI

NC_000019.10:11129601:G:T

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.

0.00040 (A)

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

Links

ClinGen: CA16602353 dbSNP: rs137853964 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	4513	4851

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	Uncertain significance (3)	reviewed by expert panel	Jan 28, 2022	RCV000417325.7
Familial hypercholesterolemia	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Jan 31, 2023	RCV001248957.11

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Jan 28, 2022) C Contributing to aggregate classification	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Hypercholesterolemia, familial, 1 (Semidominant inheritance)	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV002506346.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ad250858-bb45-464e-a96e-b94160859000 Comment: show The NM_000527.5(LDLR):c.2479G>T (p.Val827Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.86. It is above 0.75, so PP3 is met (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely pathogenic (Dec 16, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503494.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: show subject mutated among 2600 FH index cases screened = 1/previously described in association with FH/Software predictions: Conflicting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Uncertain significance (Jan 22, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial hypercholesterolemia (Autosomal dominant inheritance)	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001422751.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022	Publications: PubMed (1) PubMed: 30415195 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/bbf89fac-a7ff-4e23-a3fd-bda1d44c954b Comment: show The p.Val827Phe variant in LDLR has been reported in 2 Moroccan individuals with familial hypercholesterolemia (PMID: 30415195), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 375840). 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) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Uncertain Significance (May 30, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1 (Semidominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004828336.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (1) PubMed: 30415195 Comment: show This missense variant (also known as p.Val806Phe in the mature protein) replaces valine with phenylalanine at codon 827 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholeterolemia (PMID: 30415195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: Single Heterozygote

Likely pathogenic (Jan 31, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial hypercholesterolemia	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003472696.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 30415195 Comment: show This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 375840). This variant is also known as p.V806F. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 30415195). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 827 of the LDLR protein (p.Val827Phe). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The NM_000527.5(LDLR):c.2479G>T (p.Val827Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.86. It is above 0.75, so PP3 is met

Comment:

The p.Val827Phe variant in LDLR has been reported in 2 Moroccan individuals with familial hypercholesterolemia (PMID: 30415195), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 375840). 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 missense variant (also known as p.Val806Phe in the mature protein) replaces valine with phenylalanine at codon 827 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholeterolemia (PMID: 30415195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.

Comment:

This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 375840). This variant is also known as p.V806F. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 30415195). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 827 of the LDLR protein (p.Val827Phe).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spectrum of mutations of familial hypercholesterolemia in the 22 Arab countries.	Alhababi D	Atherosclerosis	2018	PMID: 30415195
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ad250858-bb45-464e-a96e-b94160859000	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/bbf89fac-a7ff-4e23-a3fd-bda1d44c954b	-	-	-	-

Text-mined citations for rs137853964 ...

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 15, 2026