Submissions for variant NM_000527.5(LDLR):c.-13A>G

gnomAD frequency: 0.00001  dbSNP: rs376011618

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237905	SCV005903151	uncertain significance	Hypercholesterolemia, familial, 1	2024-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.-13A>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002374 (0.0023%) in European (Non-Finnish) exomes+genomes (gnomAD v4.1.0). BS3_Supporting: Level 3 assays - PMID 25248394 (Khamis et al., 2015): Heterologous cells (Huh7), Luciferase assays: results - normal (96%) gene expression. PMID 31395865 (Kircher et al., 2019): Heterologous cells (HepG2), luciferase assays: results - 97-106% gene expression. So, BS3_Supporting is met. PP4: Variant meets PM2 and is identified in 1 case meeting Simon Broome criteria from the Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.
LDLR-LOVD, British Heart Foundation	RCV000237905	SCV000294403	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237905	SCV000322869	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Color Diagnostics, LLC DBA Color Health	RCV001186035	SCV001352365	likely benign	Familial hypercholesterolemia	2017-09-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001186035	SCV002322565	likely benign	Familial hypercholesterolemia	2023-08-30	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237905	SCV000605989	uncertain significance	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003947809	SCV004758487	likely benign	LDLR-related disorder	2019-12-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).