Submissions for variant NM_000527.5(LDLR):c.1415_1418dup (p.Gln474fs)

dbSNP: rs879254892

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238471	SCV000295417	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	RCV000238471	SCV000503345	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family members = 4
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238471	SCV000599373	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Iberoamerican FH Network	RCV000238471	SCV000748148	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000657895	SCV000779659	pathogenic	not provided	2018-06-04	criteria provided, single submitter	clinical testing	The c.1415_1418dupACAT pathogenic variant in the LDLR gene, also reported as FH Savona-1, c.1418_1419insACAT, and FS453Term515 due to the use of alternate nomenclature, is a common variant identified in at least 190 individuals with familial hypercholesterolemia (FH) from 50 unrelated Italian familes (Sun et al., 1998; Bertolini et al., 2000; Pisciotta et al., 2012). Furthermore, the c.1415_1418dupACAT variant has not been observed in large population cohorts (Lek et al., 2016). The c.1415_1418dupACAT variant causes a shift in reading frame starting at codon glutamine 474, changing it to a histidine, and creating a premature stop codon at position 63 of the new reading frame, denoted p.Gln474HisfsX63. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH, and loss of function is a known mechanism of disease for this gene (Stenson et al., 2014).
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000238471	SCV001653635	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing