Submissions for variant NM_004928.3(CFAP410):c.441_444del (p.Glu148fs)

dbSNP: rs756970705

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867534	SCV002130931	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu148Alafs*13) in the CFAP410 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFAP410 are known to be pathogenic (PMID: 23105016, 26167768). This variant is present in population databases (rs756970705, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CFAP410-related conditions. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225980	SCV003922185	likely pathogenic	Retinal dystrophy with or without macular staphyloma	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Glu148AlafsTer13 variant in CFAP410 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 428573), in one individual with rod-cone dystrophy. This individual also carried a likely pathogenic variant (ClinVar Variation ID: 428573), however the phase of these variants is unknown at this time. The p.Glu148AlafsTer13 variant in CFAP410 has not been previously reported in individuals with retinal dystrophy with or without macular staphyloma but has been identified in 0.006% (4/68028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756970705). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1368519) and has been interpreted as pathogenic by Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 148 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CFAP10 gene is an established disease mechanism in autosomal recessive retinal dystrophy with or without macular staphyloma. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive retinal dystrophy with or without macular staphyloma. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV003225980	SCV004232448	pathogenic	Retinal dystrophy with or without macular staphyloma	2024-01-17	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815694	SCV005068406	likely pathogenic	Retinal dystrophy	2020-01-01	no assertion criteria provided	clinical testing