Submissions for variant NM_000527.5(LDLR):c.1268T>C (p.Ile423Thr)

gnomAD frequency: 0.00001  dbSNP: rs879254849

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238040	SCV000295334	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	RCV000238040	SCV000503326	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 15 , family members = 6 with co-segregation / variant systematically associated with c.798T>A, p.Asp266Glu / Software predictions: Conflicting
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238040	SCV000599370	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384956	SCV001584659	pathogenic	Familial hypercholesterolemia	2020-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 423 of the LDLR protein (p.Ile423Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 7635461, 24722143, 11005141, 10884919, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.I402T in the literature. ClinVar contains an entry for this variant (Variation ID: 251760, 430765). This variant has been reported to affect LDLR protein function (PMID: 10884919). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002446477	SCV002682617	pathogenic	Cardiovascular phenotype	2018-03-06	criteria provided, single submitter	clinical testing	The p.I423T pathogenic mutation (also known as c.1268T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1268. The isoleucine at codon 423 is replaced by threonine, an amino acid with similar properties. This alteration (historically described as p.I402T) has been reported in individuals with familial hypercholesterolemia and segregated with the disease in two apparently unrelated families (Ekström U et al. MP, Mol. Pathol., 2000 Feb;53:31-6; Khoo KL et al. Clin. Genet., 2000 Aug;58:98-105; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Wu WF et al. PLoS ONE, 2014 Apr;9:e94697). In addition, functional studies have suggested that this alteration would cause reduced protein activity in LDL binding and degradation (Ekström U et al. MP, Mol. Pathol., 2000 Feb;53:31-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000238040	SCV005418438	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3+PS4_Moderate+PP4+PM3
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238040	SCV000606378	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research