Submissions for variant NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp)

gnomAD frequency: 0.00004  dbSNP: rs527236031

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000132728	SCV000957008	pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 3	2023-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 448 of the PIGT protein (p.Arg448Trp). This variant is present in population databases (rs527236031, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 24906948, 25943031). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143194). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGT protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001531960	SCV001747312	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
3billion	RCV000132728	SCV002012081	pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 3	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24906948, 25943031, 34046058, 3billion dataset, PM3_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001776, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.809, 3Cnet: 0.857, PP3). Patient's phenotype is considered compatible with Multiple congenital anomalies-hypotonia-seizures syndrome 3 (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000132728	SCV004101495	likely pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 3		criteria provided, single submitter	clinical testing	The missense variant c.1342C>T (p.Arg448Trp) in PIGT gene has been observed to segregate with multiple congenital anomalies-hypotonia-seizures syndrome in a family(Nakashima M et.al.,2014). This variant has been reported to the ClinVar database as Likely Pathogenic. The p.Arg448Trp variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.001776% is reported in gnomAD. The amino acid Arg at position 448 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg448Trp in PIGT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health	RCV000132728	SCV000187657	pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 3		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
OMIM	RCV000132728	SCV000267597	pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 3	2016-04-25	no assertion criteria provided	literature only