NM_001041.4(SI):c.3218G>A (p.Gly1073Asp) AND Sucrase-isomaltase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (13 submissions)
Last evaluated:: Apr 14, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000001484.37

Allele description [Variation Report for NM_001041.4(SI):c.3218G>A (p.Gly1073Asp)]

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

Gene:

SI:sucrase-isomaltase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q26.1

Genomic location:

Preferred name:

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

HGVS:

NC_000003.12:g.165021265C>T
NG_017043.1:g.62231G>A
NM_001041.4:c.3218G>AMANE SELECT
NP_001032.2:p.Gly1073Asp
NC_000003.11:g.164739053C>T
NM_001041.3:c.3218G>A
P14410:p.Gly1073Asp

Protein change:

G1073D; GLY1073ASP

Links:

UniProtKB: P14410#VAR_025375; OMIM: 609845.0008; dbSNP: rs121912616

NCBI 1000 Genomes Browser:

rs121912616

Molecular consequence:

NM_001041.4:c.3218G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Sucrase-isomaltase deficiency (CSID)
Synonyms:: SI DEFICIENCY; Congenital sucrose-isomaltase malabsorption; Disaccharide intolerance, 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009114; MedGen: C1283620; Orphanet: 35122; OMIM: 222900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021639	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2006)	germline	literature only	Sander, P., Alfalah, M., Keiser, M., Korponay-Szabo, I., Kovacs, J. B., Leeb, T., Naim, H. Y. Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption. Hum. Mutat. 27: 119-only, 2006.,
SCV000441975	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Mar 30, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16329100, 19121318, 23103650 Citation Link,
SCV000536853	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Pathogenic (Mar 1, 2016)	maternal	research	PubMed (2) [See all records that cite these PMIDs] 16329100, 19121318
SCV000930218	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 27, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000967637	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Apr 14, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27579322, 27872184, 23103650, 16329100, 19121318, 24033266
SCV001136628	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001445872	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 2, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001523565	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001752795	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002022580	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 9, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003929118	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19121318, 28062276, 36007526, 16329100 Citation Link,
SCV004175660	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 12, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16329100, 19121318, 23103650, 27579322, 25741868
SCV005398137	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16329100, 19121318, 23103650, 31557950, 33567694, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing
not provided	unknown	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	unknown	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.

Henström M, Diekmann L, Bonfiglio F, Hadizadeh F, Kuech EM, von Köckritz-Blickwede M, Thingholm LB, Zheng T, Assadi G, Dierks C, Heine M, Philipp U, Distl O, Money ME, Belheouane M, Heinsen FA, Rafter J, Nardone G, Cuomo R, Usai-Satta P, Galeazzi F, Neri M, et al.

Gut. 2018 Feb;67(2):263-270. doi: 10.1136/gutjnl-2016-312456. Epub 2016 Nov 21.

PubMed [citation]

PMID:: 27872184
PMCID:: PMC5563477

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000021639.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

Description

For discussion of the gly1073-to-asp (G1073D) mutation in the SI gene that was found in 2 sibs with congenital sucrase-isomaltase deficiency (CSID; 222900) by Sander et al. (2006), see 609845.0007. This mutation was also found in heterozygosity in a single patient.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000441975.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536853.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000930218.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967637.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

From Mendelics, SCV001136628.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445872.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001523565.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV001752795.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002022580.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929118.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175660.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398137.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

Relating variation to medicine