NM_001041.4:c.3218G>A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS1_Supporting
The NM_001041.4(SI):c.3218G>A(p.Gly1073Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,611,224 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SI | NM_001041.4 | c.3218G>A | p.Gly1073Asp | missense_variant | Exon 27 of 48 | ENST00000264382.8 | NP_001032.2 | |
| SI | XM_047448735.1 | c.3218G>A | p.Gly1073Asp | missense_variant | Exon 28 of 49 | XP_047304691.1 | ||
| SI | XM_047448736.1 | c.3218G>A | p.Gly1073Asp | missense_variant | Exon 28 of 49 | XP_047304692.1 | ||
| SI | XM_011513078.3 | c.3119G>A | p.Gly1040Asp | missense_variant | Exon 26 of 47 | XP_011511380.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00149 AC: 226AN: 151536Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00124 AC: 310AN: 250488Hom.: 2 AF XY: 0.00125 AC XY: 169AN XY: 135362
GnomAD4 exome AF: 0.00278 AC: 4063AN: 1459570Hom.: 6 Cov.: 31 AF XY: 0.00272 AC XY: 1977AN XY: 726122
GnomAD4 genome 0.00149 AC: 226AN: 151654Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92AN XY: 74134
ClinVar
Submissions by phenotype
Sucrase-isomaltase deficiency Pathogenic:14Uncertain:1
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. -
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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. -
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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. -
PS3;PM2;PP3;PP4 -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital sucrase-isomaltase deficiency (CSID) (MIM#222900). (I) 0108 - This gene is associated with both recessive and dominant disease. While CSID is more commonly associated with autosomal recessive, heterozygous carriers have been reported to present with a milder phenotype (PMID: 31557950). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 352 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated sucrase domain (Uniprot, PMID: 23103650). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten CSID patients, both in biallelic and heterozygous states (PMID: 16329100, 23103650, 33567694; ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrated misfolding of the mutant protein, preventing its exit from the endoplasmic reticulum. In addition, it had markedly reduced sucrase and isomaltase enzymatic activities (PMID: 19121318). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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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. -
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. -
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not provided Pathogenic:5Uncertain:1
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. -
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PS3, PM3 -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27872184, 23103650, 31589614, 36422736, 38327254, 32433684, 30609409, 33567694, 31557950, 33972906, 32732636, 36007526, 27579322, 35985447, 16329100, 19121318, 38682389, 36878682, Irlayc2024[Article]) -
PP1, PM3_strong, PS3_moderate -
Inborn genetic diseases Pathogenic:1
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SI-related disorder Pathogenic:1
The SI c.3218G>A variant is predicted to result in the amino acid substitution p.Gly1073Asp. This variant has been reported in the homozygous and compound heterozygous states as causative for congenital sucrase-isomaltase deficiency (Uhrich et al. 2012. PubMed ID: 23103650; Sander et al. 2006. PubMed ID: 16329100). Evaluation of patients homozygous for this variant revealed absence of sucrase activity in breath and blood assays (Opekun et al. 2016. PubMed ID: 27579322). Functional studies in vitro suggest absence of enzymatic activity is due to protein misfolding (Alfalah et al. 2009. PubMed ID: 19121318). This variant is reported in 0.23% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at