rs121912615

Positions:

• chr3-165046998-A-C
• chr3-165046998-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1
• Conservation: PhyloP100: 8.54

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]

ACMG classification

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=5, Pathogenic=3, Uncertain_significance=1}. 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	UniProt
SI	NM_001041.4	c.1730T>G	p.Val577Gly	missense_variant	16/48	ENST00000264382.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152142 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00158 AC XY: 210 AN XY: 132522

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.: 7 Cov.: 30 AF XY: 0.00240 AC XY: 1738 AN XY: 722932

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.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74436

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.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sucrase-isomaltase deficiency Pathogenic:7

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

not provided Pathogenic:4 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	GeneDx	Oct 04, 2023	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 (Alfalah et al., 2009); Suggested as a possible predisposition factor for irritable bowel syndrome when seen in the heterozygous state with no second SI variant (Henstrom et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in homozygous state in a patient with clinical symptoms including feeding difficulties and episodic vomiting referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 37790351, 31589614, 19121318, 27749612, 27872184, 16329100, 32433684, 30609409, 32732636, 35985447, 36167617, 35753512) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -

SI-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

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 (http://gnomad.broadinstitute.org/variant/3-164764786-A-C). 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	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.089	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.95
MPC		0.074
ClinPred		0.11	T
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

Other links and lift over

dbSNP: rs121912615; hg19: chr3-164764786; COSMIC: COSV52301193;