Submissions for variant NM_001041.4(SI):c.1730T>G (p.Val577Gly)

gnomAD frequency: 0.00131  dbSNP: rs121912615

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000481721	SCV000332703	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001483	SCV000441994	pathogenic	Sucrase-isomaltase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The SI c.1730T>G (p.Val577Gly) missense variant is documented as one of the most common pathogenic variants found in individuals with congenital sucrase-isomaltase deficiency (CSID) (Gericke et al. 2016). The p.Val577Gly variant has been reported in two individual studies in which it is found in two siblings in a compound heterozygous state and in eight individual alleles of unspecified zygosity, which represented 15% of all individual alleles in the study (Sander et al. 2006; Uhrich et al. 2012). The p.Val577Gly variant was absent from the single control tested but is reported at a frequency of 0.00139 in the European American population of the Exome Sequencing Project. The Val577 residue is conserved. Functional studies performed by Alfalah et al. (2009) show that the p.Val577Gly variant results in a protein that is misfolded with a subsequent loss of enzyme activity. The variant protein was also shown to exist exclusively as a mannose-rich glycosylated species and to be retained in the endoplasmic reticulum. Based on the evidence, the p.Val577Gly variant is classified as pathogenic for congenital sucrase-isomaltase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000481721	SCV000567692	likely pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with misfolding of the SI protein, preventing the protein from exiting the endoplasmic reticulum and resulting in loss of enzymatic function (Alfalah et al., 2009); Suggested as a possible predisposition factor for irritable bowel syndrome when seen in the heterozygous state with no second SI variant (Henstrom et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in homozygous state in a patient with clinical symptoms including feeding difficulties and episodic vomiting referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 37790351, 31589614, 19121318, 27749612, 27872184, 16329100, 32433684, 30609409, 32732636, 35985447, 36167617, 35753512)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000001483	SCV000713110	likely pathogenic	Sucrase-isomaltase deficiency	2020-03-30	criteria provided, single submitter	clinical testing	The p.Val577Gly (NM_001041.3 c.1730T>G) variant in SI has been reported in 2 compound heterozygous individuals with congenital sucrase-isomaltase deficiency (Sander 2006 and Haberman 2016), and segregated in 2 family members in 2 families (Sander 2006 and Haberman 2016). This variant has also been reported in ClinVar (Variation ID 1418). It has been identified in 0.3% (31/10004) of Ashkenazi Jewish and 0.3% of (342/126222) European chromosomes, including 1 homozygote, by gnomAD (https://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies of the p.Val577Gly variant report an impact to protein folding (Alfalah 2009). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital sucrase-isomaltase deficiency based upon biallelic occurrence in affected individuals, segregation data and functional evidence. ACMG/AMP Criteria applied: PM3_Strong, PP1, PP3, PS3_Supporting
Invitae	RCV000481721	SCV001485577	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 577 of the SI protein (p.Val577Gly). This variant is present in population databases (rs121912615, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of congenital sucrase isomaltase deficiency (CSID) (PMID: 16329100, 23103650, 27749612, 28062276). It is commonly reported in individuals of European ancestry (PMID: 23103650, 28062276). ClinVar contains an entry for this variant (Variation ID: 1418). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SI protein function. Experimental studies have shown that this missense change affects SI function (PMID: 19121318). 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.
Fulgent Genetics, Fulgent Genetics	RCV000001483	SCV001752819	likely pathogenic	Sucrase-isomaltase deficiency	2021-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000001483	SCV002022581	likely pathogenic	Sucrase-isomaltase deficiency	2023-07-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000001483	SCV003835125	likely pathogenic	Sucrase-isomaltase deficiency	2021-05-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415621	SCV004115137	pathogenic	SI-related condition	2023-05-01	criteria provided, single submitter	clinical testing	The SI c.1730T>G variant is predicted to result in the amino acid substitution p.Val577Gly. This variant was reported in multiple individuals with autosomal recessive congenital sucrase-isomaltase deficiency (Sander et al. 2006. PubMed ID: 16329100; Uhrich et al. 2012. PubMed ID: 23103650). This variant is reported in 0.31% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-164764786-A-C). This variant is interpreted as pathogenic.
OMIM	RCV000001483	SCV000021638	pathogenic	Sucrase-isomaltase deficiency	2006-01-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000001483	SCV000536852	pathogenic	Sucrase-isomaltase deficiency	2016-03-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000481721	SCV001954024	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000481721	SCV001969402	likely pathogenic	not provided		no assertion criteria provided	clinical testing