Submissions for variant NM_001041.4(SI):c.3186_3187del (p.Leu1062_Tyr1063insTer)

dbSNP: rs776569472

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479995	SCV000565905	likely pathogenic	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614)
Illumina Laboratory Services, Illumina	RCV000778684	SCV000915031	uncertain significance	Sucrase-isomaltase deficiency	2017-09-12	criteria provided, single submitter	clinical testing	The SI c.3186_3187delTT (p.Tyr1063Ter) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital sucrase-isomaltase deficiency.
Revvity Omics, Revvity	RCV000778684	SCV002022583	likely pathogenic	Sucrase-isomaltase deficiency	2020-04-02	criteria provided, single submitter	clinical testing
Invitae	RCV000479995	SCV003502046	pathogenic	not provided	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1063*) in the SI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SI are known to be pathogenic (PMID: 16329100, 23103650, 25452324). This variant is present in population databases (rs776569472, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SI-related conditions. ClinVar contains an entry for this variant (Variation ID: 418676). For these reasons, this variant has been classified as Pathogenic.