Submissions for variant NM_000527.5(LDLR):c.1294C>G (p.Leu432Val)

dbSNP: rs730882100

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237224	SCV000295347	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000161983	SCV000697194	uncertain significance	not provided	2016-09-06	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1294C>G (p.Leu432Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/120904 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in affected individuals including FH, MI, and CAD, all without strong evidence for causality (i.e. co-segregation data). In addition, LDLR-LOVD, British Heart Foundation classified this variant as likely pathogenic, without evidence to independently evaluate. One published functional study showed that overexpression of p.Leu432Val resulted in intact cellular LDL uptake comparable to wild-type, although authors did list variant as a hypomorphic variant and speculated that the compound heterozygosity of two hypomorphic variants (Y465N and L432V for example) could impair receptor activities in the range of a classic FH-mutant (Thormaehlen_2015). JoJo Genetics noted that variant of interest often co-occured with Y465N (Y444N in legacy name) although the phase not well established. Taken together and due to conflicting lines of evidence, this variant is classified as VUS until more evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001182459	SCV001347903	uncertain significance	Familial hypercholesterolemia	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Leu411Val in the mature protein) replaces leucine with valine at codon 432 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). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10090484, 15199436, 29396260, 35047021). It has also been reported in individuals affected with early-onset myocardial infarction (PMID: 25487149, 25647241) and in individuals affected with coronary artery disease (PMID: 27050191). This variant has been identified in 4/251290 chromosomes 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.
Invitae	RCV001182459	SCV001413767	likely pathogenic	Familial hypercholesterolemia	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 432 of the LDLR protein (p.Leu432Val). This variant is present in population databases (rs730882100, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10090484, 25487149, 25647241, 32770674, 35047021). This variant is also known as L411V. ClinVar contains an entry for this variant (Variation ID: 183111). 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%. 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.
Ambry Genetics	RCV002381529	SCV002689560	uncertain significance	Cardiovascular phenotype	2023-05-02	criteria provided, single submitter	clinical testing	The p.L432V variant (also known as c.1294C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1294. The leucine at codon 432 is replaced by valine, an amino acid with highly similar properties. This variant (also referred to as L411V) has been detected in hypercholesterolemia cohorts, coronary artery disease cohorts, and myocardial infarction cohorts; however, in some cases, clinical detail was limited and/or the variant co-occurred with other variants in the LDLR gene, complicating interpretation of the impact of this variant alone (Ebhardt M et al. Hum. Mutat., 1999;13:257; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Do R et al. Nature, 2015 Feb;518:102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Rieck L et al. Clin Genet. 2020 Nov;98(5):457-467; Rimbert A et al. Front Genet. 2021 Jan;12:809256). This variant One in vitro assay reported this variant to be non-disruptive to LDL uptake; however, additional evidence is needed to confirm this finding (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003895079	SCV004717204	uncertain significance	LDLR-related condition	2023-11-25	criteria provided, single submitter	clinical testing	The LDLR c.1294C>G variant is predicted to result in the amino acid substitution p.Leu432Val. This variant has also been reported in individuals with hypercholesterolemia and in controls in different reports (Thormaehlen et al. 2015. PubMed ID: 25647241; Do et al. 2015. PubMed ID: 25487149). It was also found in one individual who harbored the c.1393T>A (p.Tyr465Asn) variant that is also found in this patient, and it was suggested that together the two variants may form a hypomorphic allele, but further studies to confirm they are on the same allele were not performed (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar with interpretations of uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/183111/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161983	SCV000189558	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237224	SCV000606383	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001182459	SCV002086416	uncertain significance	Familial hypercholesterolemia	2020-02-23	no assertion criteria provided	clinical testing