ClinVar Miner

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

dbSNP: rs886041126
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000361900 SCV000329069 pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing Identified homozygous in one individual tested at GeneDx and reported as part of a cohort of individuals with suspected Mendelian, mainly neurocognitive phenotypes, undergoing exome sequencing (Yavarna et al., 2015); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26077850, 32989326, 32371413)
Invitae RCV001233636 SCV001406240 pathogenic Hereditary spastic paraplegia 50 2023-08-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg441*) in the AP4M1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acid(s) of the AP4M1 protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 26077850, 32979048, 32989326; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 279679). For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital RCV001233636 SCV001423599 likely pathogenic Hereditary spastic paraplegia 50 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].
AiLife Diagnostics, AiLife Diagnostics RCV000361900 SCV002503273 likely pathogenic not provided 2020-05-05 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001233636 SCV003815488 pathogenic Hereditary spastic paraplegia 50 2022-11-03 criteria provided, single submitter clinical testing
Institute of Human Genetics, Heidelberg University RCV001233636 SCV004037335 likely pathogenic Hereditary spastic paraplegia 50 2023-08-30 criteria provided, single submitter clinical testing
Yale Center for Mendelian Genomics, Yale University RCV001849355 SCV002106873 likely pathogenic Spastic paraplegia 2020-10-01 no assertion criteria provided literature only

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