Submissions for variant NM_001253852.3(AP4B1):c.1216C>T (p.Arg406Ter)

gnomAD frequency: 0.00001  dbSNP: rs776976178

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485345	SCV000571543	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35379322, 33594065, 34426522, 35599849, 33294911, 31915823, 31525725, 29193663)
Invitae	RCV000505223	SCV001387457	pathogenic	Hereditary spastic paraplegia 47	2023-07-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 422147). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 29193663). This variant is present in population databases (rs776976178, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg406*) in the AP4B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4B1 are known to be pathogenic (PMID: 22290197, 24700674, 24781758).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848851	SCV002105399	likely pathogenic	Hereditary spastic paraplegia	2017-01-31	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000505223	SCV002557064	pathogenic	Hereditary spastic paraplegia 47	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 47 (MIM#614066). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0701 - Many NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with spastic paraplegia 47 (ClinVar, PMID: 29193663, 33594065). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV000505223	SCV004050659	likely pathogenic	Hereditary spastic paraplegia 47	2023-04-11	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000505223	SCV000599242	likely pathogenic	Hereditary spastic paraplegia 47	2017-01-04	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849381	SCV002106826	likely pathogenic	Spastic paraplegia	2020-10-01	no assertion criteria provided	literature only