Submissions for variant NM_000527.5(LDLR):c.44T>C (p.Leu15Pro)

dbSNP: rs879254390

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237294	SCV002568023	likely pathogenic	Hypercholesterolemia, familial, 1	2022-08-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.44T>C (p.Leu15Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP4, and PS4_Supporting 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. PS3_moderate - Level 2 Assay: PMID:27175606: Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding. LDL binding <70% wild type activity, so PS3_Moderate is met. PS4_supporting - Variant meets PM2 and is identified in - 2 unrelated index cases who fulfill Simon-Broome possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), - 1 case from PMID: 12052488 with LDL-C above 10 mmol/L (DLCN>6), from Sweden. 3 cases, so PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in 3 unrelated index cases who fulfill FH clinical criteria (see PS4 for details).
LDLR-LOVD, British Heart Foundation	RCV000237294	SCV000294422	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237294	SCV000503094	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Fundacion Hipercolesterolemia Familiar	RCV000237294	SCV000607405	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001062304	SCV001227094	likely pathogenic	Familial hypercholesterolemia	2023-03-22	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. Experimental studies have shown that this missense change affects LDLR function (PMID: 27175606). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 250981). This variant is also known as L-7P. This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 12052488, 33740630, 33955087; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 15 of the LDLR protein (p.Leu15Pro).
GeneDx	RCV003128611	SCV003806057	uncertain significance	not provided	2022-08-22	criteria provided, single submitter	clinical testing	Identified in patients with FH in published literature (Lind et al., 2002; Pavlouskova et al., 2016; Leren et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect with retention of LDLR protein in the endoplasmic reticulum and no binding of LDL (Pavlouskova et al., 2016); This variant is associated with the following publications: (PMID: 28379029, 30019023, 28169869, 33740630, 12052488, 27175606, 34037665)