Submissions for variant NM_000527.5(LDLR):c.1702C>G (p.Leu568Val)

dbSNP: rs746959386

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237626	SCV000295587	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237626	SCV000484763	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237626	SCV000599380	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799671	SCV000939345	pathogenic	Familial hypercholesterolemia	2022-12-11	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 568 of the LDLR protein (p.Leu568Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10447263, 18718593, 25962062, 26510755). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.L547V. ClinVar contains an entry for this variant (Variation ID: 251976). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Leu568 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000799671	SCV001358588	likely pathogenic	Familial hypercholesterolemia	2020-01-31	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Leu547Val in the mature protein) replaces leucine with valine at codon 568 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Computational splicing tools suggest that this variant may impact RNA splicing by activating a new splice donor site. This splice prediction has not been investigated in published RNA studies. It has been shown that this variant segregates with disease in 3 related individuals from a family affected with familial hypercholesterolemia (PMID: 26510755). This variant has been reported in multiple Japanese individuals affected with familial hypercholesterolemia (PMID: 10447263, 18718593, 26632531, 31491741) and is thought to occur at 3.4% of affected individuals, compared to 0.08% minor allele frequency in the general population in Japan (PMID: 18718593). This variant has also been identified in a Korean individual affected with familial hypercholesterolemia (PMID: 26343872). Carriers of this variant show very mild clinical phenotype due to ~75% residual LDL binding activity of the mutant protein (PMID: 18718593). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics	RCV000237626	SCV002516654	pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401941	SCV002710169	likely pathogenic	Cardiovascular phenotype	2022-03-11	criteria provided, single submitter	clinical testing	The p.L568V variant (also known as c.1702C>G), located in coding exon 11 of the LDLR gene, results from a C to G substitution at nucleotide position 1702. The leucine at codon 568 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a heterozygote and compound heterozygote in familial hypercholesterolemia (FH) cohorts and has been reported in multiple family members in an affected family (Hattori H et al. Hum Mutat, 1999;14:87; Ohshiro T et al. J Atheroscler Thromb, 2010 Oct;17:1113; Miyagi Y et al. J Atheroscler Thromb, 2016 Oct;23:112-7; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Nagahara K et al. J Atheroscler Thromb, 2021 May). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000799671	SCV005204468	pathogenic	Familial hypercholesterolemia	2024-06-11	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1702C>G (p.Leu568Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251292 control chromosomes. c.1702C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and homozygous or compound heterozygous individuals show more severe and early onset of disease (Miyake_2009, Miyagi_2016, Tada_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed mild effect of this variant on LDLR-mediated LDL-binding in patient's fibroblasts in an in vitro assay (76% of wt in homozygous state and 92% of wt in heterozygous state), consistent with relative mild phenotype in homozygous or heterozygous individuals with this variant (Muyake_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31491741, 26510755, 18718593, 30241732). ClinVar contains an entry for this variant (Variation ID: 251976). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237626	SCV000606488	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research