Submissions for variant NM_000527.5(LDLR):c.1215C>G (p.Asn405Lys)

dbSNP: rs879254837

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238220	SCV000295304	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	RCV000238220	SCV000503316	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: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238220	SCV000583805	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV000791392	SCV000824745	likely pathogenic	Familial hypercholesterolemia	2018-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with lysine at codon 405 of the LDLR protein (p.Asn405Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with hypercholesterolemia, segregating with the disease in a single family (PMID: 9237502, 29576406, Invitae). This variant is also known in the literature as p.Asn384Lys. ClinVar contains an entry for this variant (Variation ID: 251738). This variant is not present in population databases (ExAC no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791392	SCV001360701	pathogenic	Familial hypercholesterolemia	2019-11-18	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1215C>G (p.Asn405Lys) 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 251046 control chromosomes (gnomAD). c.1215C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and was stated to segregate with disease in at least one family (Hernandez Flores_2018, Kotze_1997, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000238220	SCV001653628	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238220	SCV000606360	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research