NM_001041.4:c.5234T>G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BS1_SupportingBS2
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
Consequence
NM_001041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SI | NM_001041.4 | c.5234T>G | p.Phe1745Cys | missense_variant | Exon 46 of 48 | ENST00000264382.8 | NP_001032.2 | |
SI | XM_047448735.1 | c.5234T>G | p.Phe1745Cys | missense_variant | Exon 47 of 49 | XP_047304691.1 | ||
SI | XM_047448736.1 | c.5234T>G | p.Phe1745Cys | missense_variant | Exon 47 of 49 | XP_047304692.1 | ||
SI | XM_011513078.3 | c.5135T>G | p.Phe1712Cys | missense_variant | Exon 45 of 47 | XP_011511380.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00106 AC: 161AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000965 AC: 241AN: 249678Hom.: 1 AF XY: 0.000969 AC XY: 131AN XY: 135258
GnomAD4 exome AF: 0.00136 AC: 1905AN: 1395984Hom.: 4 Cov.: 29 AF XY: 0.00127 AC XY: 876AN XY: 692208
GnomAD4 genome AF: 0.00106 AC: 161AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76AN XY: 74458
ClinVar
Submissions by phenotype
Sucrase-isomaltase deficiency Pathogenic:5
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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. -
PS3;PM2;PP3;PP4 -
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
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) -
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at