ClinVar Miner

Submissions for variant NM_004595.5(SMS):c.166G>A (p.Gly56Ser) (rs121434610)

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Total submissions: 4
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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
GeneDx RCV000414369 SCV000491170 likely pathogenic not provided 2015-11-30 criteria provided, single submitter clinical testing The G56S variant in the SMS gene has been reported previously as a pathogenic variant in three males from one family with Snyder-Robinson syndrome who each inherited the variant from an unaffected mother (de Alencastro et al., 2008). The G56S 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. The G56S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Lymphoblastoid cell lines from the three patients with the G56S variant had no detectable spermine synthase enzyme activity (de Alencastro et al., 2008). In vitro studies revealed that the G56 site is sensitive to charge residue replacement, and the G56S variant was predicted to lower dimer affinity (Zhang et al., 2011). A missense variant in a nearby residue (F58L) has been reported in the Human Gene Mutation Database in association with Snyder-Robinson syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G56S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
OMIM RCV000012390 SCV000032624 pathogenic Syndromic X-linked intellectual disability Snyder type 2008-08-01 no assertion criteria provided literature only
GeneReviews RCV000012390 SCV000086910 pathologic Syndromic X-linked intellectual disability Snyder type 2013-06-27 no assertion criteria provided curation Converted during submission to Pathogenic.

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