rs121912615

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3PP5BP4

The NM_001041.4(SI):c.1730T>G(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).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

SI
NM_001041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 8.54

Variant links:

Genes affected

SI (HGNC:10856): (sucrase-isomaltase) This gene encodes a sucrase-isomaltase enzyme that is expressed in the intestinal brush border. The encoded protein is synthesized as a precursor protein that is cleaved by pancreatic proteases into two enzymatic subunits sucrase and isomaltase. These two subunits heterodimerize to form the sucrose-isomaltase complex. This complex is essential for the digestion of dietary carbohydrates including starch, sucrose and isomaltose. Mutations in this gene are the cause of congenital sucrase-isomaltase deficiency.[provided by RefSeq, Apr 2010]

SI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

PP5

Variant 3-165046998-A-C is Pathogenic according to our data. Variant chr3-165046998-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1418.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=1, Pathogenic=2}. Variant chr3-165046998-A-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.088983625). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SI	NM_001041.4 linkuse as main transcript	c.1730T>G	p.Val577Gly	missense_variant	16/48	ENST00000264382.8	NP_001032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SI	ENST00000264382.8 linkuse as main transcript	c.1730T>G	p.Val577Gly	missense_variant	16/48	1	NM_001041.4	ENSP00000264382	P1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00160

AC:

392

AN:

244938

Hom.:

AF XY:

0.00158

AC XY:

210

AN XY:

132522

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000298

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000645

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00169

GnomAD4 exome

AF:

0.00248

AC:

3601

AN:

1453278

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1738

AN XY:

722932

show subpopulations

Gnomad4 AFR exome

AF:

0.000423

Gnomad4 AMR exome

AF:

0.000296

Gnomad4 ASJ exome

AF:

0.00306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000839

Gnomad4 FIN exome

AF:

0.000808

Gnomad4 NFE exome

AF:

0.00294

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152260

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00212

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00188

AC:

228

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sucrase-isomaltase deficiency

Pathogenic:7

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, 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. -
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	Baylor Genetics	May 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -

not provided

Pathogenic:5Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	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 (PMID: 19121318, 35985447); Suggested as a possible predisposition factor for irritable bowel syndrome when seen in the heterozygous state with no second SI variant (PMID: 27872184); Observed in the homozygous state in a patient with clinical symptoms including feeding difficulties and episodic vomiting referred for genetic testing at GeneDx; 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: 37790351, 31589614, 27749612, 16329100, 32433684, 30609409, 32732636, 35985447, 36167617, 35753512, 27872184, 19121318, 37349966, 37951511, 36422736, 38682389) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2018	- -
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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SI: PM3:Strong, PM2:Supporting, PS3:Supporting -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

SI-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2024

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. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.089

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.52

MVP

0.95

MPC

0.074

ClinPred

0.11

GERP RS

5.4

Varity_R

0.95

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over