Submissions for variant NM_001253852.3(AP4B1):c.755T>C (p.Val252Ala)

gnomAD frequency: 0.00163  dbSNP: rs141417436

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425918	SCV000528655	uncertain significance	not provided	2021-01-08	criteria provided, single submitter	clinical testing	Reported in individuals with intellectual disability or persistent stuttering (Redin et al., 2014; Raza et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25167861, 26544806)
Invitae	RCV000463656	SCV000548560	likely benign	Hereditary spastic paraplegia 47	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313102	SCV000847589	uncertain significance	Inborn genetic diseases	2019-01-05	criteria provided, single submitter	clinical testing	The p.V252A variant (also known as c.755T>C), located in coding exon 5 of the AP4B1 gene, results from a T to C substitution at nucleotide position 755. The valine at codon 252 is replaced by alanine, an amino acid with similar properties. This alteration was reported in an individual with intellectual disability (Redin C et al. J. Med. Genet., 2014 Nov;51:724-36), as well as in two unrelated stuttering cases (Raza MH et al. Am. J. Hum. Genet., 2015 Nov;97:715-25). This amino acid position is highly conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000463656	SCV000894596	uncertain significance	Hereditary spastic paraplegia 47	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000425918	SCV001147384	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	AP4B1: BS1
Genetic Services Laboratory, University of Chicago	RCV001821192	SCV002069703	uncertain significance	not specified	2019-07-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848780	SCV002104884	uncertain significance	Hereditary spastic paraplegia	2020-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821192	SCV002819271	likely benign	not specified	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: AP4B1 c.755T>C (p.Val252Ala) results in a non-conservative amino acid change located in the Clathrin/coatomer adaptor, adaptin-like, N-terminal domain (IPR002553) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 247764 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.755T>C has been reported in the literature as a VUS in a heterozygous genotype along with co-occurring VUS/possibly benign variants in other genes in at-least two individuals with intellectual disability (ID) (example, Redin_2014) and in at-least two unrelated stuttering cases as well as population databases (Raza_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Spastic Paraplegia 47, Autosomal Recessive. At-least one of the cases with ID ascertained above, reported a co-occurrence with another pathogenic variant(s) (RAI1 c.2332_2336del, p.Gly778Glnfs*7) establishing an alternate molecular basis of disease and providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; likely benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003912733	SCV004735684	likely benign	AP4B1-related condition	2023-01-31	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251671	SCV001427411	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing