ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.313C>T (p.Pro105Ser) (rs13306510)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237815 SCV000294602 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Color RCV000775033 SCV000909130 uncertain significance Familial hypercholesterolemia 2018-10-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Pro84Ser in the mature protein) is a missense variant located in the second LDL-A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. The variant has been reported in individuals affected with moderate familial hypercholesterolemia in the literature (PMID 9137885 15998910 18607183). This variant is present in the general population (26/277180 chromosomes in the Genome Aggregation Database, gnomAD) primarily in the Finnish (19/25786 chromosomes). Based on available information, this variant is classified as Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000781506 SCV000919588 uncertain significance not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: LDLR c.313C>T (p.Pro105Ser) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 277426 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.313C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia including a family that suggests lack of cosegregation with disease (Vuorio_1997). These report(s) 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000775033 SCV001418365 uncertain significance Familial hypercholesterolemia 2019-01-16 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 105 of the LDLR protein (p.Pro105Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs13306510, ExAC 0.08%). This variant has been observed in several individuals with elevated cholesterol and reported to segregate with hypercholesterolemia in a family (PMID: 9137885). This variant is also described as Pro84Ser (P84S) in the literature. ClinVar contains an entry for this variant (Variation ID: 251132). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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