rs121912615

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP3PP5BP4BS1_SupportingBS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V577D) has been classified as Uncertain significance.

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:16U:1

Conservation

PhyloP100: 8.54

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

congenital sucrase-isomaltase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

SI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, 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 VariationId is 1418.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00126 (192/152260) while in subpopulation NFE AF = 0.00212 (144/68010). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SI	NM_001041.4 link	c.1730T>G	p.Val577Gly	missense_variant	Exon 16 of 48	ENST00000264382.8	NP_001032.2	P14410
SI	XM_047448735.1 link	c.1730T>G	p.Val577Gly	missense_variant	Exon 17 of 49		XP_047304691.1
SI	XM_047448736.1 link	c.1730T>G	p.Val577Gly	missense_variant	Exon 17 of 49		XP_047304692.1
SI	XM_011513078.3 link	c.1631T>G	p.Val544Gly	missense_variant	Exon 15 of 47		XP_011511380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SI	ENST00000264382.8 link	c.1730T>G	p.Val577Gly	missense_variant	Exon 16 of 48	1	NM_001041.4	ENSP00000264382.3		P14410

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

GnomAD2 exomes

AF:

0.00160

AC:

392

AN:

244938

AF XY:

0.00158

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 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

African (AFR)

AF:

0.000423

AC:

AN:

33126

American (AMR)

AF:

0.000296

AC:

AN:

43968

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.000839

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.000808

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00294

AC:

3252

AN:

1107440

Other (OTH)

AF:

0.00210

AC:

126

AN:

59986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

149

298

446

595

744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152260

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41572

American (AMR)

AF:

0.000589

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00212

AC:

144

AN:

68010

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00223

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:16Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sucrase-isomaltase deficiency

Pathogenic:10

May 24, 2021

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM3_Strong+PP4+PP3+PS3_Moderate -

Jul 05, 2024

Aleixo Muise Laboratory, Hospital For Sick Children

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PS3;PM2;PP3;PP4 -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Jan 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 18, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 30, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 (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 -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:5Uncertain:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 07, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, Irlayc2024[Article], 38327254) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SI: PM3:Strong, PM2:Supporting, PS3:Supporting -

Aug 31, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SI-related disorder

Pathogenic:1

Apr 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

8.5

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

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over