Submissions for variant NM_000527.5(LDLR):c.311G>A (p.Cys104Tyr) (rs875989895)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211701	SCV000294598	likely pathogenic	Familial hypercholesterolemia 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	RCV000211701	SCV000503129	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000211701	SCV000540724	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys89 and Cys104.
Invitae	RCV001046101	SCV001209989	pathogenic	Familial hypercholesterolemia	2019-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 104 of the LDLR protein (p.Cys104Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 15359125, 22883975, Invitae). This variant is also described as C83Y in the literature. ClinVar contains an entry for this variant (Variation ID: 226315). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Cys104 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV001046101	SCV001482199	pathogenic	Familial hypercholesterolemia	2021-02-01	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.311G>A (p.Cys104Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.311G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Kim_2004, Hooper_2012, Kusters_2013). These data indicate that the variant is likely to be associated with disease. The C104 residue is one of the cysteines forming intra-repeat disulfide bonds in repeat 2 of the ApoB-binding domain (Hobbs et al., 1990), indicating structural importance to codon 104. Additionally, several other variants at codon 104 have been reported in association with hypercholesterolemia (C104R, C104F, C104W; HGMD). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211701	SCV000268552	pathogenic	Familial hypercholesterolemia 1	2008-07-22	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211701	SCV000606073	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research