Submissions for variant NM_000527.5(LDLR):c.980A>C (p.His327Pro)

dbSNP: rs2077361686

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV001255944	SCV004022470	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.980A>C (p.His327Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755 The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.954 PP4 - Variant meet PM2. PMID: 31345425 (Trinder et al., 2019), Canada - 1 case with clinical Dutch Lipid Clinic Network Criteria score >= 6.
Color Diagnostics, LLC DBA Color Health	RCV001175869	SCV001339654	uncertain significance	Familial hypercholesterolemia	2019-10-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.His306Pro in the mature protein) replaces histidine with proline at codon 327 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. 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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV001255944	SCV001432621	likely pathogenic	Hypercholesterolemia, familial, 1	2018-12-07	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001175869	SCV003339130	uncertain significance	Familial hypercholesterolemia	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 327 of the LDLR protein (p.His327Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 31345425, 35913489; internal data). ClinVar contains an entry for this variant (Variation ID: 918325). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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.