Submissions for variant NM_024700.4(SNIP1):c.1097A>G (p.Glu366Gly)

gnomAD frequency: 0.00008  dbSNP: rs387906986

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219947	SCV001391914	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 366 of the SNIP1 protein (p.Glu366Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive syndromic epilepsy and skull dysplasia (PMID: 22279524, 34570759). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30717). 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 SNIP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SNIP1 function (PMID: 22279524). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000023695	SCV001976578	likely pathogenic	Psychomotor retardation, epilepsy, and craniofacial dysmorphism	2022-03-22	criteria provided, single submitter	clinical testing	The SNIP1 c.1097A>G p.(Glu366Gly) missense variant results in substitution of glutamic acid at amino acid position 366 with glycine. This variant has been reported in a homozygous state in at least 35 individuals from 21 interrelated Old Order Amish families diagnosed with neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures, with segregation noted in several families (Puffenbuerger et al. 2012; Ammous et al. 2021). This variant is reported in the Genome Aggregation Database in ten alleles at a frequency of 0.01096 in the Amish population (version 3.1.2). The variant is present in the C-terminus portion of the protein, which is known to interact with c-Myc, SMAD1 and SMAD2 (Puffenberger et al. 2012). Transient overexpression of wild-type and p.Glu353Gly Snip1 mouse protein (corresponding to human p.Glu366Gly protein) in mIMCD3 cells revealed the mutant protein to have a more aggregated appearance as compared to wild-type protein and also resulted in decreased protein levels suggestive of an unstable protein (Puffenberger et al. 2012). Multiple lines of computational evidence suggest the variant may have a deleterious impact on the gene or gene product. Based on the available evidence the c.1097A>G p.(Glu366Gly) variant is classified as likely pathogenic for neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures.
Ambry Genetics	RCV004018669	SCV003553169	uncertain significance	not specified	2020-12-22	criteria provided, single submitter	clinical testing	The c.1097A>G (p.E366G) alteration is located in exon 4 (coding exon 4) of the SNIP1 gene. This alteration results from a A to G substitution at nucleotide position 1097, causing the glutamic acid (E) at amino acid position 366 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD), the SNIP1 c.1097A>G alteration was not observed, with coverage at this position. This alteration was reported homozygous in two Amish brothers with severe psychomotor delay, intractable seizures, bulbous nose, wide mouth and tongue, broad jaw with protuberant angles, short hands, short tapered fingers, and broad thumbs. A brain MRI showed enlarged ventricles, a thin corpus callosum, hypomyelination, and an irregular, undulating skull surface (Puffenberger, 2012). The p.E366 amino acid is conserved in available vertebrate species. The in silico prediction for the p.E366G alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM	RCV000023695	SCV000044986	pathogenic	Psychomotor retardation, epilepsy, and craniofacial dysmorphism	2012-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758597	SCV005352799	likely pathogenic	SNIP1-related disorder	2024-06-22	no assertion criteria provided	clinical testing	The SNIP1 c.1097A>G variant is predicted to result in the amino acid substitution p.Glu366Gly. This variant has been reported in the homozygous state in three Old Order Amish patients with symptomatic epilepsy and skull dysplasia (Puffenberger et al. 2012. PubMed ID: 22279524). An additional large study detected this variant in the homozygous state in thirty-five affected Old Order Amish individuals with a neurodevelopmental disorder and varied clinical phenotypes (Ammous et al 2021. PubMed ID: 34570759). An in vitro mouse model found this variant results in a more aggregated localization in the nucleus compared to wild type and Western blot analysis suggested it is unstable (Puffenberger et al. 2012. PubMed ID: 22279524). Analysis of >5,000 Amish control samples indicated an allele frequency of 0.5% (Pennsylvania Amish) to 1.4% (Ohio/Indiana/Wisconsin Amish) in this founder population with no unaffected individuals being homozygous for this variant (Ammous et al 2021. PubMed ID: 34570759; Puffenberger et al. 2012. PubMed ID: 22279524). In summary, we interpret this variant as likely pathogenic.