Submissions for variant NM_001128126.3(AP4S1):c.289C>T (p.Arg97Ter)

gnomAD frequency: 0.00009  dbSNP: rs200440467

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443008	SCV000521309	pathogenic	not provided	2023-03-24	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; This variant is associated with the following publications: (PMID: 25552650, 29302074, 31130284, 32371413, 33644862, 32895917, 32979048, 31345219, 27535533, 28708303)
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000223666	SCV000586778	likely pathogenic	Spastic paraplegia 52, autosomal recessive	2017-01-06	criteria provided, single submitter	clinical testing	Intellectual disability, moderate; acquired microcephaly (-4SD); hypotonia; epilepsy (starting at 2 months old)
Genetic Services Laboratory, University of Chicago	RCV000443008	SCV000593255	pathogenic	not provided	2021-01-29	criteria provided, single submitter	clinical testing
Invitae	RCV000525844	SCV000629434	pathogenic	Spastic paraplegia	2023-08-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234924). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 25552650). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs200440467, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg97*) in the AP4S1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4S1 are known to be pathogenic (PMID: 21620353, 25552650, 27444738).
Eurofins Ntd Llc (ga)	RCV000443008	SCV000859814	pathogenic	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000223666	SCV001368406	pathogenic	Spastic paraplegia 52, autosomal recessive	2019-04-02	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000223666	SCV001423591	pathogenic	Spastic paraplegia 52, autosomal recessive	2019-02-22	criteria provided, single submitter	clinical testing	[ACMG/AMP: PVS1, PM2, PM3, PP1] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], has been shown to cosegregate with disease in multiple affected family members [PP1].
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260893	SCV001437993	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000443008	SCV001447536	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000223666	SCV001478364	pathogenic	Spastic paraplegia 52, autosomal recessive	2019-12-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223666	SCV002021412	pathogenic	Spastic paraplegia 52, autosomal recessive	2022-07-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000223666	SCV002792570	pathogenic	Spastic paraplegia 52, autosomal recessive	2022-02-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000223666	SCV004175975	pathogenic	Spastic paraplegia 52, autosomal recessive	2023-11-09	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM3,PM2_SUP
OMIM	RCV000223666	SCV000280013	pathogenic	Spastic paraplegia 52, autosomal recessive	2018-06-21	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV001249232	SCV001423167	not provided	AP4S1-related disorder		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Yale Center for Mendelian Genomics, Yale University	RCV000525844	SCV002106897	likely pathogenic	Spastic paraplegia	2020-10-01	no assertion criteria provided	literature only