Submissions for variant NM_001041.4(SI):c.3218G>A (p.Gly1073Asp)

gnomAD frequency: 0.00150  dbSNP: rs121912616

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000001484	SCV000441975	pathogenic	Sucrase-isomaltase deficiency	2018-03-30	criteria provided, single submitter	clinical testing	The SI c.3218G>A (p.Gly1073Asp) missense variant has been identified in individuals with congenital sucrase-isomaltase deficiency (CSID), including in a compound heterozygous state in two individuals and in a heterozygous state in one individual in whom a second variant was not identified (Sander et al. 2006). Uhrich et al. (2012) identified the p.Gly1073Asp variant on 17/62 CSID individual alleles and indicated that at least 11 individuals carried the variant in a homozygous or compound heterozygous state. Control data was not available for the p.Gly1073Asp variant, which is reported at a frequency of 0.00233 in the European-American population of the Exome Sequencing Project. Functional studies using COS cells transfected with wild type or variant SI plasmids demonstrated that the p.Gly1073Asp variant prevents the SI protein from exiting the endoplasmic reticulum, and that the variant disrupts the folding and enzymatic activity of the essential sucrase and isomaltase domains (Alfalah et al. 2009). Based on the evidence, the p.Gly1073Asp 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.
Ambry Genetics	RCV000622702	SCV000742924	pathogenic	Inborn genetic diseases	2017-10-04	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000001484	SCV000930218	uncertain significance	Sucrase-isomaltase deficiency	2019-04-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000001484	SCV000967637	likely pathogenic	Sucrase-isomaltase deficiency	2020-04-14	criteria provided, single submitter	clinical testing	The p.Gly1073Asp (NM_001041.3 c.3218G>A) variant in SI has been reported in at least 14 compound heterozygous or homozygous individuals with congenital sucrase-isomaltase deficiency, and segregated with disease in one affected sibling (Sander 2006 PMID: 16329100, UIhrich 2012 PMID: 23103650, Opekun 2016 PMID: 27579322). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 1419). It has also been identified in 0.23% (297/128400) of European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org), however, this frequency is low enough to be consistent with a recessive carrier frequency. Enzymatic studies conducted on patient samples suggest that the p.Gly1073Asp variant confers absence of sucrase activity (Opekun 2016 PMID: 27579322) and in vitro functional studies of the variant report an impact to protein folding along with reduced activity (Alfalah 2009 PMID: 19121318). 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, although additional studies are required to fully establish its clinical significance, the p.Gly1073Asp variant is likely pathogenic for sucrase-isomaltase deficiency in an autosomal recessive manner based upon biallelic occurrence in affected individuals, segregation data and functional evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3, PP1.
Mendelics	RCV000001484	SCV001136628	pathogenic	Sucrase-isomaltase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000001484	SCV001445872	likely pathogenic	Sucrase-isomaltase deficiency	2019-10-02	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in patients with congenital sucrase-isomaltase deficiency (PMID: 16329100, 19121318, 23103650). Functional studies have demonstrated that the c.3218G>A (p.Gly1073Asp) variant results in protein misfolding, the inability of the protein to exit the endoplasmic reticulum, and reduced enzymatic activity (PMID: 19121318). In the gnomAD population database, this variant is present in the heterozygous state at a frequency of 0.13% (356/281,824) and is present in the homozygous state in two individuals. This variant has been reported in the ClinVar database (Variation ID: 1419). The c.3218G>A (p.Gly1073Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3218G>A (p.Gly1073Asp) variant is classified as Pathogenic.
Invitae	RCV001324096	SCV001515037	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1073 of the SI protein (p.Gly1073Asp). This variant is present in population databases (rs121912616, gnomAD 0.2%), 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) and has been described as one of the four variants commonly observed in individuals of European ancestry diagnosed with CSID (PMID: 16329100, 23103650, 28062276). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1419). 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.
Baylor Genetics	RCV000001484	SCV001523565	likely pathogenic	Sucrase-isomaltase deficiency	2021-05-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000001484	SCV001752795	likely pathogenic	Sucrase-isomaltase deficiency	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001324096	SCV001758226	likely pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant results in misfolding, altered trafficking, and loss of enzyme activity (Alfalah et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19121318, 27872184, 23103650, 31589614, 32433684, 30609409, 33567694, 31557950, 33972906, 32732636, 27579322, 16329100, 36007526)
Revvity Omics, Revvity	RCV000001484	SCV002022580	likely pathogenic	Sucrase-isomaltase deficiency	2020-10-09	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001324096	SCV002051692	likely pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing	PS3, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001484	SCV003929118	likely pathogenic	Sucrase-isomaltase deficiency	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: SI c.3218G>A (p.Gly1073Asp) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 250488 control chromosomes in the gnomAD database, including 2 homozygotes. c.3218G>A has been reported in the literature in multiple individuals affected with Sucrase-Isomaltase Deficiency (Sander_2006, Gericke_2017, Kingsmore_2022), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function, finding <10% of normal enzymatic activity as well as disruption of folding and transport from the endoplasmic reticulum (Alfalah_2009, Gericke_2017). 13 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=11) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000001484	SCV004175660	likely pathogenic	Sucrase-isomaltase deficiency	2023-04-12	criteria provided, single submitter	clinical testing	The SI c.3218G>A variant is classified as a LIKELY PATHOGENIC variant (PS3, PM2, PP3) The variant is a single nucleotide change in exon 27/48 of the SI gene, which is predicted to change the amino acid glycine at position 1073 in the protein to aspartic acid. The variant has been previously detected in multiple unrelated individuals with Congenital sucrase-isomaltase deficiency in compound heterozygous or homozygous state (PMID: 16329100, 19121318, 23103650). Functional studies have demostrated that the variant disrupt the protein folding along with reduced enzymatic activity (PMID: 27579322, 19121318) (PS3). The variant is in dbSNP (rs121912616) and has been reported in population databases (gnomAD: 226/151536, 0 homozygote) at a frequency that is consistent with a recessive carrier frequency (PM2). The variant has been reported by other laboratories and HGMD (Accession no.: CM0604720) with conflicting interpretations of pathogenicity (3 Pathogenic; 7 Likely Pathogenic; 2 VUS) (Clinvar Variation ID: #1419). Computational predictions support a deleterious effect on the gene or gene product (PP3). Clinical review is recommended.
OMIM	RCV000001484	SCV000021639	pathogenic	Sucrase-isomaltase deficiency	2006-01-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000001484	SCV000536853	pathogenic	Sucrase-isomaltase deficiency	2016-03-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001324096	SCV001952111	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001324096	SCV001973762	likely pathogenic	not provided		no assertion criteria provided	clinical testing