ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.251C>G (p.Pro84Arg)

dbSNP: rs875989892
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237248 SCV004022400 uncertain significance Hypercholesterolemia, familial, 1 2023-03-20 reviewed by expert panel curation The NM_000527.5(LDLR):c.251C>G (p.Pro84Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 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 - This variant is absent from gnomAD (gnomAD v2.1.1).: PP4 - Variant meets PM2 and is identified in one index case from PMID 16159606 who fulfill SB criteria for FH.
LDLR-LOVD, British Heart Foundation RCV000237248 SCV000294555 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV002518473 SCV003258651 pathogenic Familial hypercholesterolemia 2022-09-09 criteria provided, single submitter clinical testing This variant disrupts the p.Pro84 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 22883975, 33740630), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 251095). This variant is also known as P63R. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 16159606, 33740630; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the LDLR protein (p.Pro84Arg).

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