VCV001518023.8 - ClinVar

NM_000527.5(LDLR):c.1307T>A (p.Val436Glu)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (2)

2 out of 2 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.1307T>A (p.Val436Glu)

Variation ID: 1518023 Accession: VCV001518023.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11113398 (GRCh38) [ NCBI UCSC ] 19: 11224074 (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 28, 2022	Feb 23, 2026	Apr 26, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1307T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Val436Glu	missense
NM_001195798.2:c.1307T>A	NP_001182727.1:p.Val436Glu	missense
NM_001195799.2:c.1184T>A	NP_001182728.1:p.Val395Glu	missense
NM_001195800.2:c.803T>A	NP_001182729.1:p.Val268Glu	missense
NM_001195803.2:c.926T>A	NP_001182732.1:p.Val309Glu	missense
NC_000019.10:g.11113398T>A
NC_000019.9:g.11224074T>A
NG_009060.1:g.29018T>A
LRG_274:g.29018T>A
LRG_274t1:c.1307T>A

... more HGVS ... less HGVS

Protein change

V309E, V268E, V436E, V395E

Other names

Canonical SPDI

NC_000019.10:11113397:T:A

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: CA404085099 dbSNP: rs779732323 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	4627	4969

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.
Familial hypercholesterolemia	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2022	RCV002041241.6
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	May 9, 2019	RCV002386926.2

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.	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.
Likely pathogenic (May 09, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002693562.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 22081141 Comment: show The p.V436E variant (also known as c.1307T>A), located in coding exon 9 of the LDLR gene, results from a T to A substitution at nucleotide position 1307. The valine at codon 436 is replaced by glutamic acid, an amino acid with dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this codon, p.V436A, has been reported in individuals with familial hypercholesterolemia (FH), shown to co-segregate with disease, and reported to result in deficient LDL-receptor expression (Lombardi P et al. Clin. Genet., 1997 Apr;51:286-7; Selberg O et al. J Appl Res., 2003;3:495-504; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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

Likely pathogenic (Apr 26, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial hypercholesterolemia	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002309243.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 21722902‚ 30270359‚ 9184256 Comment: show This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 436 of the LDLR protein (p.Val436Glu). 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. This variant disrupts the p.Val436 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9184256, 21722902, 30270359), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). It has also been observed to segregate with disease in related individuals. (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 p.V436E variant (also known as c.1307T>A), located in coding exon 9 of the LDLR gene, results from a T to A substitution at nucleotide position 1307. The valine at codon 436 is replaced by glutamic acid, an amino acid with dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this codon, p.V436A, has been reported in individuals with familial hypercholesterolemia (FH), shown to co-segregate with disease, and reported to result in deficient LDL-receptor expression (Lombardi P et al. Clin. Genet., 1997 Apr;51:286-7; Selberg O et al. J Appl Res., 2003;3:495-504; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 436 of the LDLR protein (p.Val436Glu). 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. This variant disrupts the p.Val436 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9184256, 21722902, 30270359), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). It has also been observed to segregate with disease in related individuals.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.	Alver M	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30270359
Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.	Lo Surdo P	EMBO reports	2011	PMID: 22081141
Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.	Vaca G	Atherosclerosis	2011	PMID: 21722902
A novel V415A mutation in exon 9 of the low density lipoprotein receptor gene causing familial hypercholesterolemia.	Lombardi P	Clinical genetics	1997	PMID: 9184256

Text-mined citations for rs779732323 ...

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 Apr 04, 2026