Submissions for variant NM_000527.5(LDLR):c.1328G>C (p.Trp443Ser)

dbSNP: rs879254866

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238264	SCV005688655	likely pathogenic	Hypercholesterolemia, familial, 1	2025-01-31	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1328G>C (p.Trp443Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0000006841 (0.00006841 %) in European (non-Finnish) exomes (gnomAD version 4.1.0). PP3: REVEL = 0.934. PM5: 1 other missense variant in the same codon: NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) (ClinVar ID 251792)- Pathogenic by these guidelines. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 9 unrelated index cases who fulfill criteria for FH: 1 case meeting Simon Broome criteria from PMID 17142622 (Humphries et al., 2006), UK; 1 case meeting Simon Broome possible FH criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 3 cases with DLCN >=6 from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France; 4 cases with DLCN >=6 from PMID 34871818 (Tada et al., 2022), Japan.
LDLR-LOVD, British Heart Foundation	RCV000238264	SCV000295369	likely pathogenic	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	RCV000238264	SCV000503333	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: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238264	SCV000583821	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000238264	SCV000607586	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238264	SCV000606395	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research