ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2113G>C (p.Ala705Pro)

gnomAD frequency: 0.00001  dbSNP: rs193922570
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000030132 SCV002506399 uncertain significance Hypercholesterolemia, familial, 1 2022-02-11 reviewed by expert panel curation The NM_000527.5 (LDLR): c.2113G>C (p.Ala705Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, 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 Met: PopMAX MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, PMID 11810272). PP3 Met: REVEL score = 0.78, which is above the threshold of 0.75. PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>T (p.Ala705Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000722114 SCV000052787 pathogenic Familial hypercholesterolemia 2017-09-25 criteria provided, single submitter clinical testing Variant summary: The c.2113G>C (p.Ala705Pro) in LDLR gene is a missense variant involves a highly conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured here due to low reliability index value) predict deleterious outcome. However, no functional studies supporting these predictions were published at the time of evaluation. The c.2113G>C is present in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245716 chromosomes tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0012, suggesting that it is not a common polymorphism. The variant has been reported in multiple affected individuals with FH, including one patient, who carried R3500Q in APOB with lipid profile suggestive of being a carrier of two pathogenic variants. The variant reportedly classified as having a delayed (2B) transport from the endoplasmic reticulum to the cell surface, but is cited as VUS by reputable databases/clinical laboratories. Lastly, the codon Ala705 appears to be a hot spot, and another alteration, c.2113G>T (p.Ala705Ser) has been reported in association with Hypercholesterolaemia. Taken together the variant was classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000030132 SCV000295878 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV000722114 SCV000627026 pathogenic Familial hypercholesterolemia 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 705 of the LDLR protein (p.Ala705Pro). This variant is present in population databases (rs193922570, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11810272, 18325082, 21382890, 22095935, 23375686, 25412742). This variant is also known as p.A684P. ClinVar contains an entry for this variant (Variation ID: 36459). 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.Ala705 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15556093), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001537549 SCV001754443 likely pathogenic not provided 2023-04-17 criteria provided, single submitter clinical testing A large study of individuals from the Netherlands with FH-related variants concluded that LDL-C levels were significantly higher in A705P carriers compared to non-carriers (Huijgen et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18325082, 21382890, 23369702, 23375686, 22390909, 20506408, 27919364, 21642693, 22095935, 23833242, 32719484, 34037665, 11810272)
Ambry Genetics RCV002415431 SCV002725259 pathogenic Cardiovascular phenotype 2021-10-01 criteria provided, single submitter clinical testing The p.A705P pathogenic mutation (also known as c.2113G>C), located in coding exon 14 of the LDLR gene, results from a G to C substitution at nucleotide position 2113. The alanine at codon 705 is replaced by proline, an amino acid with highly similar properties. This alteration, also referred to as A684P, has been detected in multiple individuals from Dutch familial hypercholesterolemia (FH) cohorts with elevated mean LDL-C level compared to controls; however, in some cases, clinical details were limited (Fouchier SW et al. Hum Genet. 2001;109:602-15; Huijgen R et al. Circ Cardiovasc Genet. 2011;4:413-7; van der Graaf A et al. Circulation. 2011;123:1167-73). This alteration was also seen in an Italian FH cohort (Bertolini S et al. Atherosclerosis. 2013;227:342-8). In one family, this alteration segregated with hypercholesterolemia in two individuals, but was also detected in two relatives without elevated cholesterol (Huijgen R et al. Hum Mutat. 2012;33:448-55). In another report, this alteration was seen in conjunction with an APOB mutation in a patient with untreated LDL-C level of 9.6mmol/L (Sjouke B et al. J Clin Lipidol. 2016;10:1462-1469). Another alteration affecting this amino acid (p.A705S) has also been detected in an FH cohort (Humphries SE. J Med Genet. 2006;43(12):943-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV000030132 SCV003830907 likely pathogenic Hypercholesterolemia, familial, 1 2023-05-22 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000030132 SCV004822569 uncertain significance Hypercholesterolemia, familial, 1 2023-12-01 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000030132 SCV000606601 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000030132 SCV000733829 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV001537549 SCV001922288 pathogenic not provided no assertion criteria provided clinical testing

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