Submissions for variant NM_004722.4(AP4M1):c.923C>G (p.Ser308Ter)

dbSNP: rs1131691556

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493866	SCV000582378	pathogenic	not provided	2015-09-24	criteria provided, single submitter	clinical testing	The S308X variant in the AP4M1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S308X 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. Protein truncating variants downstream of S308X have been reported in the Human Gene Mutation Database in association with autosomal recessive spastic tetraplegia (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. We interpret S308X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003114618	SCV003789151	pathogenic	Hereditary spastic paraplegia 50	2022-06-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser308*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AP4M1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429735). For these reasons, this variant has been classified as Pathogenic.