VCV002203459.4 - ClinVar

NM_001041.4(SI):c.273_274del (p.Gly92fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001041.4(SI):c.273_274del (p.Gly92fs)

Variation ID: 2203459 Accession: VCV002203459.4

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 3q26.1 3: 165069177-165069178 (GRCh38) [ NCBI UCSC ] 3: 164786965-164786966 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Oct 8, 2024	Oct 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001041.4:c.273_274del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001032.2:p.Gly92fs	frameshift
NM_001041.4:c.273_274delAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001041.3:c.273_274delAG
NC_000003.12:g.165069177CT[2]
NC_000003.11:g.164786965CT[2]
NG_017043.1:g.14314AG[2]

... more HGVS ... less HGVS

Protein change

G92fs

Other names

Canonical SPDI

NC_000003.12:165069176:CTCTCT:CTCT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SI		-	-	GRCh38 GRCh37	1255	1276

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 19, 2023	RCV002651759.3
Sucrase-isomaltase deficiency	Pathogenic (1)	criteria provided, single submitter	Oct 25, 2023	RCV003404134.1
SI-related disorder	Pathogenic (1)	no assertion criteria provided	May 6, 2024	RCV004750308.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 25, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Sucrase-isomaltase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004122116.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Publications: PubMed (1) PubMed: 25452324 Comment: Variant summary: SI c.273_274delAG (p.Gly92LeufsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: SI c.273_274delAG (p.Gly92LeufsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250802 control chromosomes. c.273_274delAG has been reported in the literature in at least one homozygous individual affected with Sucrase-Isomaltase Deficiency (e.g.Mercadier_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25452324). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Jul 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003525386.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 25452324‚ 16329100‚ 23103650 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with congenital sucrase-isomaltase deficiency (PMID: … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with congenital sucrase-isomaltase deficiency (PMID: 25452324). This variant is present in population databases (rs781470490, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly92Leufs*8) 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). (less)
Pathogenic (May 06, 2024)	no assertion criteria provided Method: clinical testing	SI-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005345253.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SI c.273_274delAG variant is predicted to result in a frameshift and premature protein termination (p.Gly92Leufs8). This variant has been reported in an individual with … (more) The SI c.273_274delAG variant is predicted to result in a frameshift and premature protein termination (p.Gly92Leufs8). This variant has been reported in an individual with sucrase isomaltase deficiency and is a known founder variant in Inuit populations, with an allele frequency of 17.2% (Marcadier et al 2015. PubMed ID: 25452324). Frameshift variants in SI are expected to be pathogenic, and therefore we interpret c.273_274del (p.Gly92Leufs*8) as pathogenic. (less)

Comment:

Variant summary: SI c.273_274delAG (p.Gly92LeufsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250802 control chromosomes. c.273_274delAG has been reported in the literature in at least one homozygous individual affected with Sucrase-Isomaltase Deficiency (e.g.Mercadier_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25452324). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with congenital sucrase-isomaltase deficiency (PMID: 25452324). This variant is present in population databases (rs781470490, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly92Leufs*8) 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).

Comment:

The SI c.273_274delAG variant is predicted to result in a frameshift and premature protein termination (p.Gly92Leufs*8). This variant has been reported in an individual with sucrase isomaltase deficiency and is a known founder variant in Inuit populations, with an allele frequency of 17.2% (Marcadier et al 2015. PubMed ID: 25452324). Frameshift variants in SI are expected to be pathogenic, and therefore we interpret c.273_274del (p.Gly92Leufs*8) as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation.	Marcadier JL	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2015	PMID: 25452324
Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID.	Uhrich S	Journal of pediatric gastroenterology and nutrition	2012	PMID: 23103650
Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption.	Sander P	Human mutation	2006	PMID: 16329100

Text-mined citations for this variant ...

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001041.4(SI):c.273_274del (p.Gly92fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...