Submissions for variant NM_018418.5(SPATA7):c.1183C>T (p.Arg395Ter)

gnomAD frequency: 0.00001  dbSNP: rs75895925

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001291573	SCV001480108	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001462	SCV001585102	pathogenic	Leber congenital amaurosis 3	2023-03-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPATA7 protein in which other variant(s) (p.Asn454Lysfs*2) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1397). This premature translational stop signal has been observed in individuals with juvenile-onset retinitis pigmentosa (PMID: 19268277, 21602930). This variant is present in population databases (rs75895925, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg395*) in the SPATA7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 205 amino acid(s) of the SPATA7 protein.
GeneDx	RCV001291573	SCV002820712	pathogenic	not provided	2023-01-06	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 205 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD; ); This variant is associated with the following publications: (PMID: 20301475, 32799588, 27422788, 25525159, 19268277, 31908400, 32141364, 27375279, 25814828, 21310915, 21602930, 20104588, 31589614)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003485517	SCV004242053	pathogenic	Leber congenital amaurosis	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: SPATA7 c.1183C>T (p.Arg395X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.8e-05 in 250134 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPATA7 causing Leber Congenital Amaurosis (4.8e-05 vs 0.00087), allowing no conclusion about variant significance. c.1183C>T has been reported either at a homozygous state or in trans along with a second pathogenic variant in at-least three individuals affected with early-onset ocular diseases including poor vision, ocular digital sign, fundus changes of attenuated vessels, tapetoretinal degeneration, retina degeneration, and/or extinguished ERG recording of rods and cones (example, Xiao_2019). These data indicate that the variant is likely to be associated with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31908400). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Dept Of Ophthalmology, Nagoya University	RCV003887848	SCV004707785	likely pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
OMIM	RCV002260581	SCV000021617	pathogenic	Retinitis pigmentosa 94, variable age at onset	2009-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000001462	SCV000086977	not provided	Leber congenital amaurosis 3		no assertion provided	literature only
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000001462	SCV001432525	pathogenic	Leber congenital amaurosis 3		no assertion criteria provided	research