Submissions for variant NM_004722.4(AP4M1):c.1012C>T (p.Arg338Ter)

gnomAD frequency: 0.00004  dbSNP: rs146262009

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191922	SCV002236504	pathogenic	Hereditary spastic paraplegia 50	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg338*) in the AP4M1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4M1 are known to be pathogenic (PMID: 24700674, 25496299, 25558065). This variant is present in population databases (rs146262009, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with spastic paraplegia (PMID: 24700674, 28464862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209980). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003227707	SCV003924753	pathogenic	not provided	2022-12-02	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: 31589614, 34402213, 25496299, 24700674, 25558065, 32979048, 28464862)
3billion	RCV000191922	SCV004013549	pathogenic	Hereditary spastic paraplegia 50		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000209980 / PMID: 24700674). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000191922	SCV000246145	pathogenic	Hereditary spastic paraplegia 50	2014-07-01	no assertion criteria provided	literature only
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	RCV000191922	SCV001481940	likely pathogenic	Hereditary spastic paraplegia 50	2020-01-01	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849336	SCV002106860	likely pathogenic	Spastic paraplegia	2020-10-01	no assertion criteria provided	literature only
Clinical Genetics Laboratory, CHRU Nancy	RCV000191922	SCV002547281	pathogenic	Hereditary spastic paraplegia 50		no assertion criteria provided	clinical testing