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

dbSNP: rs886041126

Total submissions: 8

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)
Labcorp Genetics (formerly Invitae), Labcorp	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
CeGaT Center for Human Genetics Tuebingen	RCV000361900	SCV005075532	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	AP4M1: PM2, PVS1:Moderate
Yale Center for Mendelian Genomics, Yale University	RCV001849355	SCV002106873	likely pathogenic	Spastic paraplegia	2020-10-01	no assertion criteria provided	literature only