rs121912615
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3PP5BP4
The NM_001041.4(SI):āc.1730T>Gā(p.Val577Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,605,538 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V577D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SI | NM_001041.4 | c.1730T>G | p.Val577Gly | missense_variant | 16/48 | ENST00000264382.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SI | ENST00000264382.8 | c.1730T>G | p.Val577Gly | missense_variant | 16/48 | 1 | NM_001041.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00126 AC: 192AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00160 AC: 392AN: 244938Hom.: 1 AF XY: 0.00158 AC XY: 210AN XY: 132522
GnomAD4 exome AF: 0.00248 AC: 3601AN: 1453278Hom.: 7 Cov.: 30 AF XY: 0.00240 AC XY: 1738AN XY: 722932
GnomAD4 genome ? AF: 0.00126 AC: 192AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67AN XY: 74436
ClinVar
Submissions by phenotype
Sucrase-isomaltase deficiency Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The SI c.1730T>G (p.Val577Gly) missense variant is documented as one of the most common pathogenic variants found in individuals with congenital sucrase-isomaltase deficiency (CSID) (Gericke et al. 2016). The p.Val577Gly variant has been reported in two individual studies in which it is found in two siblings in a compound heterozygous state and in eight individual alleles of unspecified zygosity, which represented 15% of all individual alleles in the study (Sander et al. 2006; Uhrich et al. 2012). The p.Val577Gly variant was absent from the single control tested but is reported at a frequency of 0.00139 in the European American population of the Exome Sequencing Project. The Val577 residue is conserved. Functional studies performed by Alfalah et al. (2009) show that the p.Val577Gly variant results in a protein that is misfolded with a subsequent loss of enzyme activity. The variant protein was also shown to exist exclusively as a mannose-rich glycosylated species and to be retained in the endoplasmic reticulum. Based on the evidence, the p.Val577Gly 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 24, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 30, 2020 | The p.Val577Gly (NM_001041.3 c.1730T>G) variant in SI has been reported in 2 compound heterozygous individuals with congenital sucrase-isomaltase deficiency (Sander 2006 and Haberman 2016), and segregated in 2 family members in 2 families (Sander 2006 and Haberman 2016). This variant has also been reported in ClinVar (Variation ID 1418). It has been identified in 0.3% (31/10004) of Ashkenazi Jewish and 0.3% of (342/126222) European chromosomes, including 1 homozygote, by gnomAD (https://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies of the p.Val577Gly variant report an impact to protein folding (Alfalah 2009). 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, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital sucrase-isomaltase deficiency based upon biallelic occurrence in affected individuals, segregation data and functional evidence. ACMG/AMP Criteria applied: PM3_Strong, PP1, PP3, PS3_Supporting - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2006 | - - |
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 | Revvity Omics, Revvity | Jul 18, 2023 | - - |
not provided Pathogenic:4Uncertain:1
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Published functional studies demonstrate a damaging effect with misfolding of the SI protein, preventing the protein from exiting the endoplasmic reticulum and resulting in loss of enzymatic function (Alfalah et al., 2009); Suggested as a possible predisposition factor for irritable bowel syndrome when seen in the heterozygous state with no second SI variant (Henstrom et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in homozygous state in a patient with clinical symptoms including feeding difficulties and episodic vomiting referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 37790351, 31589614, 19121318, 27749612, 27872184, 16329100, 32433684, 30609409, 32732636, 35985447, 36167617, 35753512) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 577 of the SI protein (p.Val577Gly). This variant is present in population databases (rs121912615, gnomAD 0.3%), 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) (PMID: 16329100, 23103650, 27749612, 28062276). It is commonly reported in individuals of European ancestry (PMID: 23103650, 28062276). ClinVar contains an entry for this variant (Variation ID: 1418). 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 | May 01, 2023 | The SI c.1730T>G variant is predicted to result in the amino acid substitution p.Val577Gly. This variant was reported in multiple individuals with autosomal recessive congenital sucrase-isomaltase deficiency (Sander et al. 2006. PubMed ID: 16329100; Uhrich et al. 2012. PubMed ID: 23103650). This variant is reported in 0.31% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-164764786-A-C). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at