Submissions for variant NM_000527.5(LDLR):c.2479G>T (p.Val827Phe)

dbSNP: rs137853964

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000417325	SCV002506346	uncertain significance	Hypercholesterolemia, familial, 1	2022-01-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.2479G>T (p.Val827Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.86. It is above 0.75, so PP3 is met
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417325	SCV000503494	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/previously described in association with FH/Software predictions: Conflicting
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248957	SCV001422751	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Val827Phe variant in LDLR has been reported in 2 Moroccan individuals with familial hypercholesterolemia (PMID: 30415195), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 375840). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248957	SCV003472696	likely pathogenic	Familial hypercholesterolemia	2023-01-31	criteria provided, single submitter	clinical testing	This variant is also known as p.V806F. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 375840). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 30415195). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 827 of the LDLR protein (p.Val827Phe).
All of Us Research Program, National Institutes of Health	RCV000417325	SCV004828336	uncertain significance	Hypercholesterolemia, familial, 1	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Val806Phe in the mature protein) replaces valine with phenylalanine at codon 827 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholeterolemia (PMID: 30415195). This variant has not been identified 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.