Submissions for variant NM_001253852.3(AP4B1):c.1160_1161del (p.Thr387fs)

dbSNP: rs587779388

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623767	SCV000742035	pathogenic	Inborn genetic diseases	2016-11-30	criteria provided, single submitter	clinical testing
Invitae	RCV000144484	SCV000822690	pathogenic	Hereditary spastic paraplegia 47	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr387Argfs*30) 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). This variant is present in population databases (rs587779388, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with AP4B1-related conditions (PMID: 24781758). ClinVar contains an entry for this variant (Variation ID: 156414). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001008108	SCV001167858	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Observed in homozygous state in several unrelated patients in published literature with hypotonia, spastic paraplegia, microcephaly, severe intellectual disability, and global developmental delay and not observed in homozygous state in controls (PMID: 32166732, 24781758); Reported with a second AP4B1 variant in an individual with SPG47 in the published literature (PMID: 29193663); Frameshift 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; This variant is associated with the following publications: (PMID: 24781758, 21620353, 21440262, 22290197, 25552650, 25693842, 24700674, 19559397, 23167973, 20972249, 23472171, 31525725, 32166732, 31915823, 33728854, 32895917, 32964447, 33726816, 34544818, 34729478, 29193663)
CeGaT Center for Human Genetics Tuebingen	RCV001008108	SCV001249619	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	AP4B1: PVS1, PM3:Strong, PM2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000144484	SCV001369530	pathogenic	Hereditary spastic paraplegia 47	2019-09-04	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP5. This variant was detected in homozygous state.
Paris Brain Institute, Inserm - ICM	RCV000144484	SCV001451161	pathogenic	Hereditary spastic paraplegia 47		criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814068	SCV001755280	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001008108	SCV002064319	pathogenic	not provided	2021-01-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000144484	SCV002557266	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 (37 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). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
MGZ Medical Genetics Center	RCV000144484	SCV002580721	pathogenic	Hereditary spastic paraplegia 47	2022-05-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000144484	SCV004050663	likely pathogenic	Hereditary spastic paraplegia 47	2023-04-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000144484	SCV000119895	pathogenic	Hereditary spastic paraplegia 47	2012-01-01	no assertion criteria provided	research	In two siblings who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia we detected the novel homozygous 2 bp deletion c.1159_1160delCA in AP4B1; the mutation was present in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47 (SPG47).
OMIM	RCV000144484	SCV000256543	pathogenic	Hereditary spastic paraplegia 47	2014-04-30	no assertion criteria provided	literature only
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251672	SCV001427412	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001008108	SCV001953329	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001008108	SCV001964319	pathogenic	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849316	SCV002106831	likely pathogenic	Spastic paraplegia	2020-10-01	no assertion criteria provided	literature only