Submissions for variant NM_000527.5(LDLR):c.828C>A (p.Cys276Ter)

dbSNP: rs146651743

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000172961	SCV004022433	pathogenic	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.828C>A (p.Cys276Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PM3, PP1, PP4) 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: -PVS1: Variant is predicted to result in a stop codon at amino acid 276, which is amino-terminal of amino acid 830. -PS4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID: 32977124, homozygous FH; 1 cases with SB possible FH from PMID: 26036859, and 1 case with FH by MedPed criteria from PMID 21310417). -PM2: This variant is absent from gnomAD (gnomAD v2.1.1). -PM3: Variant identified as homozygous state in an index case with homozygous FH phenotype from PMID: 32977124. -PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). -PP4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID: 32977124, homozygous FH; 1 cases with SB possible FH from PMID: 26036859, and 1 case with FH by MedPed criteria from PMID 21310417), after alternative causes of high cholesterol were excluded.
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172961	SCV000212136	likely benign	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research
LDLR-LOVD, British Heart Foundation	RCV000172961	SCV000295004	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000172961	SCV000540763	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000172961	SCV000607507	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Mendelics	RCV000172961	SCV001140982	pathogenic	Hypercholesterolemia, familial, 1	2023-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384763	SCV001584408	pathogenic	Familial hypercholesterolemia	2023-04-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189298). This premature translational stop signal has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 10790219). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys276*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000172961	SCV005417159	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4+PP4
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000172961	SCV000606240	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research