3-165021265-C-T

Position:

chr3-165021265-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

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

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 6 hom. )

Consequence

SI
NM_001041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:2

Conservation

PhyloP100: 5.37

Variant links:

Genes affected

SI (HGNC:10856): (sucrase-isomaltase) This gene encodes a sucrase-isomaltase enzyme that is expressed in the intestinal brush border. The encoded protein is synthesized as a precursor protein that is cleaved by pancreatic proteases into two enzymatic subunits sucrase and isomaltase. These two subunits heterodimerize to form the sucrose-isomaltase complex. This complex is essential for the digestion of dietary carbohydrates including starch, sucrose and isomaltose. Mutations in this gene are the cause of congenital sucrase-isomaltase deficiency.[provided by RefSeq, Apr 2010]

SI links:

SI (HGNC:):

SI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 3-165021265-C-T is Pathogenic according to our data. Variant chr3-165021265-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1419.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=4, Likely_pathogenic=10}. Variant chr3-165021265-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-165021265-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.41911948). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SI	NM_001041.4 linkuse as main transcript	c.3218G>A	p.Gly1073Asp	missense_variant	27/48	ENST00000264382.8	NP_001032.2	P14410

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SI	ENST00000264382.8 linkuse as main transcript	c.3218G>A	p.Gly1073Asp	missense_variant	27/48	1	NM_001041.4	ENSP00000264382.3		P14410

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

226

AN:

151536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000595

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00124

AC:

310

AN:

250488

Hom.:

AF XY:

0.00125

AC XY:

169

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.000864

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00278

AC:

4063

AN:

1459570

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1977

AN XY:

726122

show subpopulations

Gnomad4 AFR exome

AF:

0.000630

Gnomad4 AMR exome

AF:

0.000560

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00346

Gnomad4 OTH exome

AF:

0.00211

GnomAD4 genome

AF:

0.00149

AC:

226

AN:

151654

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.000651

Gnomad4 AMR

AF:

0.000595

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00275

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00146

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00114

AC:

139

EpiCase

AF:

0.00169

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sucrase-isomaltase deficiency

Pathogenic:12Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 30, 2018	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. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 12, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 09, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Oct 02, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

not provided

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 24, 2024	PP1, PM3_strong, PS3_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 19, 2021	PS3, PM3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2017

- -

SI-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.077

MetaRNN

Benign

0.42

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.86

MVP

0.67

MPC

0.25

ClinPred

0.14

GERP RS

4.6

Varity_R

0.94

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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