ClinVar Miner

Submissions for variant NM_001128126.3(AP4S1):c.289C>T (p.Arg97Ter) (rs200440467)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443008 SCV000521309 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The R97X variant in the AP4S1 gene has been reported previously in the compound heterozygous state, opposite of a second pathogenic variant, in two sisters with arrested development at the onset of infantile febrile seizures, late childhood-onset tonic seizures, abnormal brain MRI and EEG with background slowing, profound intellectual disability, axial hypotonia, spastic diparesis, facial hypotonia, and dysmorphic features (Hardies et al., 2015). The R97X variant has also been reported as a homozygous change in an individual with epilepsy, intellectual disability, acquired microcephaly, and hypotonia (Cherot et al., 2017). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R97X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
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 RCV000501216 SCV000593255 uncertain significance not specified 2015-11-10 criteria provided, single submitter clinical testing
Invitae RCV000525844 SCV000629434 pathogenic Spastic paraplegia 2017-06-19 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs200440467, ExAC 0.03%). This variant has been reported in the compound heterozygous state with a second pathogenic variant in two siblings affected with infantile onset seizures, severe developmental delay, and spastic paraplegia (PMID: 25552650). ClinVar contains an entry for this variant (Variation ID: 234924). Loss-of-function variants in AP4S1 are known to be pathogenic (PMID: 21620353, 25552650, 27444738). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 University RCV000223666 SCV001478364 pathogenic Spastic paraplegia 52, autosomal recessive 2019-12-19 criteria provided, single submitter clinical testing
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.

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