Submissions for variant NM_000271.5(NPC1):c.688_693del (p.Ser230_Val231del) (rs758687942)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000492895	SCV000344636	uncertain significance	not provided	2016-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000492895	SCV000581824	pathogenic	not provided	2017-04-28	criteria provided, single submitter	clinical testing	The c.688_693delTCTGTG variant has been reported previously in association with Niemann-Pickdisease, type C (NPC) in patients who also harbored a second variant in the NPC1 gene (Sun et al.,2001; Imrie et al., 2015). The c.688_693delTCTGTG variant causes the loss of a Serine codon atposition 230 and the loss of a Valine codon at position 231, denoted p.Ser230_Val231. Thec.688_693delTCTGTG variant is not observed at a significant frequency in large population cohorts(Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysispredicts this variant is probably damaging to the protein structure/function. In summary, we interpretc.688_693delTCTGTG as pathogenic.
Counsyl	RCV000669390	SCV000794138	uncertain significance	Niemann-Pick disease type C1	2017-09-15	criteria provided, single submitter	clinical testing
Invitae	RCV000669390	SCV001410264	likely pathogenic	Niemann-Pick disease type C1	2019-10-31	criteria provided, single submitter	clinical testing	This variant, c.688_693del, results in the deletion of 2 amino acid(s) of the NPC1 protein (p.Ser230_Val231del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758687942, ExAC 0.01%). This variant has been observed in individuals affected with NPC1-related conditions (PMID: 11349231, 19744920, 26666848). ClinVar contains an entry for this variant (Variation ID: 290134). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.