Submissions for variant NM_004595.5(SMS):c.166G>A (p.Gly56Ser)

dbSNP: rs121434610

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210586	SCV000262966	pathogenic	Inborn genetic diseases	2013-07-15	criteria provided, single submitter	clinical testing	​SMS c.166G>A (p.G56S):The c.166G>A (p.G56S) alteration is located in exon 2 of the SMS gene. This alteration results from a G to A substitution at nucleotide position 166. The glycine (G) at codon 56 is replaced by serine (S).The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the SMS c.166G>A (p.G56S) alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. The alteration is currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP) as rs121434610.The altered amino acid is conserved throughout evolution:The p.G56 amino acid is conserved throughout vertebrates.in silico prediction is conflicting:The p.G56S alteration is predicted to be benign by Polyphen and by SIFT in silico analyses. However, structure-based computational analysis predicts that the p.G56S alteration reduces the affinity of monomers to form a dimer and leads to structural reorganization and destabilization of the SMS monomer (Zhang et al, 2010). Further, computational analysis involving binding free energycalculations predict a decrease in dimer affinity with any substitution at amino acid G56 (Zhang et al., 2011).The amino acid is located in a functionally important protein domain:The p.G56 amino acid is located in the N-terminal region of the SMS protein, which is essential for proper dimerisation and ability to catalyze spermine from spermidine (Ikeguchi et al., 2006; de Alencastro et al., 2008).The amino acid change has been observed in affected individuals:The p.G56S alteration is reported in the HGMD database (CM083784). The alteration co-segregated in a large Brazilian kindred with Snyder-Robinson syndrome with marked clinical variability and was not identified among 724 control chromosomes (de Alencastro et al., 2008). Female carriers manifested skewed X-inactivation, consistent with the original Snyder-Robinson syndrome family(de Alencastro et al., 2008).Functional analysis reveals a damaging effect of the amino acid alteration:Analysis of immortalizedlymphoblastoid cell lines (LCL) in patients with the p.G56S alterationrevealeda marked decrease in enzyme activity(de Alencastro et al., 2008). Further, in vitro analysis involving site-directed mutagenesis and western blot analysis demonstrated that the G56S alteration resulted in a reduction in dimers formation as compared to wild type (Zhang et al., 2011).Based on the available evidence, the SMS c.166G>A (p.G56S) alteration is classified as a pathogenic mutation.de Alencastro, et al. (2008) J Med Genet 45:539-543.Zhang Z, et al. (2010) Hum Mutat 31(9):1043–1049.Zhang Z, et al. (2011) PLoS One 6(5):e20373.
GeneDx	RCV000414369	SCV000491170	pathogenic	not provided	2022-10-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as in vitro studies reveal the G56 site is sensitive to charge residue replacement with the G56S variant predicted to lower dimer affinity (Zhang et al., 2011) In addition, lymphoblastoid cell lines from affected males had no detectable spermine synthase enzyme activity (de Alencastro et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20556796, 23408511, 18550699, 26761001, 26350204, 30237987, 23805436, 31580924, 21647366)
OMIM	RCV000012390	SCV000032624	pathogenic	Syndromic X-linked intellectual disability Snyder type	2008-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000012390	SCV000086910	not provided	Syndromic X-linked intellectual disability Snyder type		no assertion provided	literature only