ClinVar Miner

Submissions for variant NM_001041.4(SI):c.1730T>G (p.Val577Gly) (rs121912615)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000481721 SCV000332703 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000001483 SCV000441994 pathogenic Sucrase-isomaltase deficiency 2017-04-27 criteria provided, single submitter clinical testing 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.
GeneDx RCV000481721 SCV000567692 likely pathogenic not provided 2021-04-13 criteria provided, single submitter clinical testing Suggested as a possible predisposition factor for irritable bowel syndrome when seen in the heterozygous state with no second SI variant (Henstrm et al., 2018); Published functional studies demonstrate that V577G leads to misfolding of the SI protein, preventing the protein from exiting the endoplasmic reticulum and resulting in loss of enzymatic function (Alfalah et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30609409, 16329100, 27872184, 27749612, 19121318, 32433684)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000001483 SCV000713110 likely pathogenic Sucrase-isomaltase deficiency 2020-03-30 criteria provided, single submitter clinical testing 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 ( 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
Invitae RCV000481721 SCV001485577 uncertain significance not provided 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 577 of the SI protein (p.Val577Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs121912615, ExAC 0.3%), including at least one homozygous and/or hemizygous individual. This variant 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, 27749612, 23103650, 28062276). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1418). This variant has been reported to affect SI protein function (PMID: 19121318). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Fulgent Genetics,Fulgent Genetics RCV000001483 SCV001752819 likely pathogenic Sucrase-isomaltase deficiency 2021-06-30 criteria provided, single submitter clinical testing
OMIM RCV000001483 SCV000021638 pathogenic Sucrase-isomaltase deficiency 2006-01-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000001483 SCV000536852 pathogenic Sucrase-isomaltase deficiency 2016-03-01 no assertion criteria provided research

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