ClinVar Miner

Submissions for variant NM_004722.4(AP4M1):c.1321C>T (p.Arg441Ter) (rs886041126)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000361900 SCV000329069 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing The R441X variant in the AP4M1 gene has been reported as homozygous in one individual with epilepsy and microcephaly from a consanguineous Qatari family (Yavarna et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation. The R441X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R441X as a pathogenic variant.
Invitae RCV001233636 SCV001406240 uncertain significance Spastic paraplegia 50, autosomal recessive 2019-07-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the AP4M1 gene (p.Arg441*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acids of the AP4M1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with microcephaly and epilepsy (PMID: 26077850). ClinVar contains an entry for this variant (Variation ID: 279679). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV001233636 SCV001423599 likely pathogenic Spastic paraplegia 50, autosomal recessive 2018-09-13 criteria provided, single submitter clinical testing [ACMG/AMP: PM2, PM3, PP3, PP5] This alteration is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

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