NM_000527.5(LDLR):c.1307T>C (p.Val436Ala) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 25, 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:: RCV001063423.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1307T>C (p.Val436Ala)]

NM_000527.5(LDLR):c.1307T>C (p.Val436Ala)

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.1307T>C (p.Val436Ala)

HGVS:

NC_000019.10:g.11113398T>C
NG_009060.1:g.29018T>C
NM_000527.5:c.1307T>CMANE SELECT
NM_001195798.2:c.1307T>C
NM_001195799.2:c.1184T>C
NM_001195800.2:c.803T>C
NM_001195803.2:c.926T>C
NP_000518.1:p.Val436Ala
NP_000518.1:p.Val436Ala
NP_001182727.1:p.Val436Ala
NP_001182728.1:p.Val395Ala
NP_001182729.1:p.Val268Ala
NP_001182732.1:p.Val309Ala
LRG_274t1:c.1307T>C
LRG_274:g.29018T>C
LRG_274p1:p.Val436Ala
NC_000019.9:g.11224074T>C
NM_000527.4:c.1307T>C
c.1307T>C

Protein change:

V268A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000340; dbSNP: rs779732323

NCBI 1000 Genomes Browser:

rs779732323

Molecular consequence:

NM_000527.5:c.1307T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1307T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1184T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.803T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.926T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295357	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (7) [See all records that cite these PMIDs] 21382890, 25412742, 30270359, 33740630, 34407635, 9184256, 21722902 Citation Link,
SCV001228267	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9184256, 21382890, 21722902, 33740630, 28492532
SCV001733658	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9184256, 21382890, 21722902, 34407635, 25741868
SCV005045747	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement.

Fouchier SW, Hutten BA, Defesche JC.

J Med Genet. 2015 Feb;52(2):80-4. doi: 10.1136/jmedgenet-2014-102653. Epub 2014 Nov 20.

PubMed [citation]

PMID:: 25412742

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

Alver M, Palover M, Saar A, Läll K, Zekavat SM, Tõnisson N, Leitsalu L, Reigo A, Nikopensius T, Ainla T, Kals M, Mägi R, Gabriel SB, Eha J, Lander ES, Irs A, Philippakis A, Marandi T, Natarajan P, Metspalu A, Kathiresan S, Esko T.

Genet Med. 2019 May;21(5):1173-1180. doi: 10.1038/s41436-018-0311-2. Epub 2018 Oct 1.

PubMed [citation]

PMID:: 30270359
PMCID:: PMC6443485

See all PubMed Citations (9)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295357.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (7)
2	not provided	1	not provided	not provided	literature only	PubMed (7)

Description

Re-evaluation of AGMC classification, scoring PP1_strong, PM2 and PS4_moderate. PP3 can not be scored as the REVEL value is 0.746 (below the >0.75 threshold).

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001228267.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 436 of the LDLR protein (p.Val436Ala). This variant is present in population databases (rs779732323, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 9184256, 21382890, 21722902, 33740630; Invitae). This variant is also known as V415A. ClinVar contains an entry for this variant (Variation ID: 251778). 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 with a positive predictive value of 95%. This variant disrupts the p.Val436 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001733658.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Val415Ala in the mature protein) replaces valine with alanine in the LDLR type B repeat 1 at codon 436 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 observed in over 40 individuals affected with familial hypercholesterolemia, including 42 Dutch carriers with LDL-C levels in the 75-88th percentile (PMID: 9184256, 21382890, 21722902, 34407635; Hartgers 2020, dissertation, University of Amsterdam). This variant has been reported to segregate with hypercholesterolemia in ten individuals from a Dutch family (PMID: 9184256). This variant has been identified in 4/282608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV005045747.1

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

Description

The c.1307T>C (p.Val436Ala) variant in the LDLR gene is located on the exon 9 and is predicted to replace valine with alanine at codon 436 (p.Val436Ala). The variant has been identified in 3 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 21382890, 21722902, 9184256). The variant segregates with FH phenotype in 10 informative meiosis in a family (PMID: 9184256). The variant has been reported in ClinVar (ID: 251778). The variant is rare in the general population according to gnomAD (4/282608). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.75). Therefore, the c.1307T>C (p.Val436Ala) variant of LDLR has been classified as likely pathogenic.

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

Last Updated: Sep 29, 2024

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