rs79717168

Positions:

chr3-164983015-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2

The ENST00000264382.8(SI):c.5234T>G(p.Phe1745Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,548,244 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 4 hom. )

Consequence

SI
ENST00000264382.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 4.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP5

Variant 3-164983015-A-C is Pathogenic according to our data. Variant chr3-164983015-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1417.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SI	NM_001041.4 linkuse as main transcript	c.5234T>G	p.Phe1745Cys	missense_variant	46/48	ENST00000264382.8	NP_001032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SI	ENST00000264382.8 linkuse as main transcript	c.5234T>G	p.Phe1745Cys	missense_variant	46/48	1	NM_001041.4	ENSP00000264382	P1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000965

AC:

241

AN:

249678

Hom.:

AF XY:

0.000969

AC XY:

131

AN XY:

135258

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.000466

Gnomad ASJ exome

AF:

0.00269

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000371

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00136

AC:

1905

AN:

1395984

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

876

AN XY:

692208

show subpopulations

Gnomad4 AFR exome

AF:

0.000155

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000405

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152260

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00100

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.000948

AC:

115

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.000951

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sucrase-isomaltase deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SI c.5234T>G (p.Phe1745Cys) missense variant has been identified in individuals with congenital sucrase-isomaltase deficiency (CSID), including in a compound heterozygous state in at least four individuals and in a heterozygous state in two individuals in whom a second variant was not identified (Sander et al. 2006; Lucke et al. 2009). Uhrich et al. (2012) identified the p.Phe1745Cys variant in five out of 31 individuals with CSID, or an allele frequency of 0.08. Control data is not available for this variant, which is reported at a frequency of 0.00209 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.Phe1745Cys variant disrupts the trafficking of the SI protein out of the endoplasmic reticulum, and that the variant disrupts the folding and enzymatic activity of the essential sucrase domain of the SI protein (Alfalah et al. 2009). Based on the evidence, the p.Phe1745Cys 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	literature only	OMIM	Jan 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a compound heterozygous change in patients with congenital sucrase-isomaltase deficiency and a heterozygous change in individuals with increased risk for irritable bowel syndrome and abnormally low sucrase activity (PMID: 16329100, 19121318, 27872184, 32732636, 31557950, 33567694). Functional studies showed that the c.5234T>G (p.Phe1745Cys) variant resulted in protein misfolding (PMID: 19121318, 25525159). The c.5234T>G (p.Phe1745Cys) variant is present in the gnomAD population database at a frequency of 0.096% (270/281086) in the heterozygous state and a frequency of 0.00035% (1/281086) in the hemizygous state. The c.5234T>G (p.Phe1745Cys) variant affects a weakly 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.5234T>G (p.Phe1745Cys) variant is classified as Likely Pathogenic. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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: 20981092, 25525159, 19121318, 32732636, 16329100, 27872184, 33567694) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1745 of the SI protein (p.Phe1745Cys). This variant is present in population databases (rs79717168, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with 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, 19680155, 23103650, 28062276). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1417). 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. -

SI-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The SI c.5234T>G variant is predicted to result in the amino acid substitution p.Phe1745Cys. This variant has been reported in the compound heterozygous state and along with other SI variants (phase not known) in individuals with congenital sucrose-isomaltase deficiency (CSID) (Sander et al. 2006. PMID: 16329100; Alfalah et al. 2009. PMID: 19121318; Lücke et al. 2009. PubMed ID: 19680155; Uhrich et al. 2012. PubMed ID: 23103650; Esposito et al. 2021. PubMed ID: 33567694). This variant has been reported in the heterozygous state in individuals with functional gastrointestinal disorders including functional abdominal pain (FAP), irritable bowel syndrome with diarrhea (IBS-D), IBS mixed phenotype (IBS-M), functional dyspepsia (FD), and non-erosive reflux disease (NERD) (Henström et al. 2018. PubMed ID: 27872184; Table S2 and S3, Deb et al. 2021. PubMed ID: 32732636). A study of individuals heterozygous for the p.Phe1745Cys variant showed that all individuals tested had abnormally low sucrase levels (Table S2 and S3, Deb et al. 2021. PubMed ID: 32732636). An analysis of the SI protein showed that the p.Phe1745Cys variant altered protein folding and abolished sucrase and isomaltase/palatinase activity (Alfalah et al. 2009. PubMed ID: 19121318; Gericke et al. 2017. PubMed ID: 28062276). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, was also present in the 1000 genomes data, however no specific information was provided for those tested (Supplementary Table 5, 1000 Genomes Project. 2010. PubMed ID: 20981092), and has been reported in control populations (Henström et al. 2018. PubMed ID: 27872184). CSID is commonly known to be inherited in a homozygous or compound heterozygous manner (Naim et al. 2012. PubMed ID: 23103643), therefore this variant is pathogenic for autosomal recessive disease. However, heterozygous carriers of known rare CSID variants, including the p.Phe1745Cys variant, may be at an increased risk of mild forms of CSID or IBS (Henström et al. 2018. PubMed ID: 27872184; Husein et al. 2019. PubMed ID: 31557950), therefore this variant is uncertain in regards to autosomal dominant SI-related disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.00029

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.44

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MVP

0.98

MPC

0.060

ClinPred

0.13

GERP RS

4.9

Varity_R

0.74

gMVP

0.85

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

Other links and lift over