Submissions for variant NM_000527.5(LDLR):c.1577C>A (p.Pro526His)

dbSNP: rs879254944

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV002279959	SCV002568117	uncertain significance	Hypercholesterolemia, familial, 1	2022-01-18	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1577C>A (p.Pro526His) variant is classified as variant of Uncertain significance 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). PP3 - REVEL = 0.946.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589406	SCV000697202	uncertain significance	not provided	2016-07-22	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1577C>A (p.Pro526His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120246 control chromosomes. This variant has been reported in one FH patient. Functional studies assessing the impact the variant may have on the LDLR protein were not published at the time of classification. Due to the the lack of clinical information and the absence of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530906	SCV003442674	likely pathogenic	Familial hypercholesterolemia	2022-11-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Pro526 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11462246, 25647241, 27497240; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 496019). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 24082139, 33418990; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 526 of the LDLR protein (p.Pro526His).
Ambry Genetics	RCV004992368	SCV005609293	likely pathogenic	Cardiovascular phenotype	2024-10-03	criteria provided, single submitter	clinical testing	The p.P526H variant (also known as c.1577C>A), located in coding exon 10 of the LDLR gene, results from a C to A substitution at nucleotide position 1577. The proline at codon 526 is replaced by histidine, an amino acid with similar properties. This variant was reported in individuals with features consistent with familial hypercholesterolemia (FH) (Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62; Meshkov A et al. Genes (Basel), 2021 Jan;12:[ePub ahead of print]; Ambry internal data). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.