rs79717168

chr3-164983015-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_001041.4(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 NM_001041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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: {Pathogenic=2, Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SI	NM_001041.4	c.5234T>G	p.Phe1745Cys	missense_variant	46/48	ENST00000264382.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152142 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000969 AC XY: 131 AN XY: 135258

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.: 4 Cov.: 29 AF XY: 0.00127 AC XY: 876 AN XY: 692208

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.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74458

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.: 0

Bravo AF: 0.00100

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000948 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.000951

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sucrase-isomaltase deficiency Pathogenic:3

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. -
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	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2023	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	Invitae	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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 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	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.98
MPC		0.060
ClinPred		0.13	T
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

Other links and lift over

dbSNP: rs79717168; hg19: chr3-164700803;