Submissions for variant NM_000527.5(LDLR):c.451G>C (p.Ala151Pro)

gnomAD frequency: 0.00001  dbSNP: rs763233960

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238165	SCV000294721	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000484918	SCV000568520	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(A130P); This variant is associated with the following publications: (PMID: 18325082, 15701167, 17990524, 11642133, 19062533, 33418990, 30583242, 34906454, 16792510)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781509	SCV000919591	uncertain significance	not specified	2018-12-11	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.451G>C (p.Ala151Pro) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245930 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.451G>C, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Zakharova_2005). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518476	SCV003259877	uncertain significance	Familial hypercholesterolemia	2022-02-22	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 151 of the LDLR protein (p.Ala151Pro). This variant is present in population databases (rs763233960, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11642133, 16792510; Invitae). This variant is also known as p.Ala130Pro. ClinVar contains an entry for this variant (Variation ID: 251234). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003298312	SCV004000133	uncertain significance	Cardiovascular phenotype	2023-05-31	criteria provided, single submitter	clinical testing	The p.A151P variant (also known as c.451G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 451. The alanine at codon 151 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in subjects with familial hypercholesterolemia (FH), though limited clinical information was available (Leigh SE et al. Ann Hum Genet, 2008 Jul;72:485-98; Lombardi MP et al. Genet Test, 2006;10:77-84; Zakharova FM et al. BMC Med Genet, 2005 Feb;6:6; Meshkov A et al. Genes (Basel), 2021 Jan;12:). This amino acid position is not 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.
All of Us Research Program, National Institutes of Health	RCV000238165	SCV005426447	uncertain significance	Hypercholesterolemia, familial, 1	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 151 of the LDLR protein. This variant is also known as p.Ala130Pro in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with familial hypercholesterolemia (PMID: 11642133, 16792510; ClinVar SCV003259877.1). This variant has been identified in 3/251146 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238165	SCV000606124	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research