rs200401846

chr22-32099272-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000343.4(SLC5A1):c.1370A>G(p.Gln457Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,461,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q457H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000040 (1 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.30

Genes affected

SLC5A1 (HGNC:11036): (solute carrier family 5 member 1) This gene encodes a member of the sodium-dependent glucose transporter (SGLT) family. The encoded integral membrane protein is the primary mediator of dietary glucose and galactose uptake from the intestinal lumen. Mutations in this gene have been associated with glucose-galactose malabsorption. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a mutagenesis_site Strong reduction in D-glucose transporter activity. (size 0) in uniprot entity SC5A1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC5A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 22-32099272-A-G is Pathogenic according to our data. Variant chr22-32099272-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 529229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A1	NM_000343.4	c.1370A>G	p.Gln457Arg	missense_variant	12/15	ENST00000266088.9
SLC5A1	NM_001256314.2	c.989A>G	p.Gln330Arg	missense_variant	11/14
SLC5A1	XM_011530331.2	c.1281-2750A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A1	ENST00000266088.9	c.1370A>G	p.Gln457Arg	missense_variant	12/15	1	NM_000343.4	P1
SLC5A1	ENST00000543737.2	c.989A>G	p.Gln330Arg	missense_variant	11/14	2
SLC5A1	ENST00000477969.1	n.536A>G		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251456 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461754 Hom.: 1 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SLC5A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

The SLC5A1 c.1370A>G variant is predicted to result in the amino acid substitution p.Gln457Arg. This variant has been reported in the homozygous state in multiple related individuals with glucose-galactose malabsorption (GGM) and was shown to co-segregate with disease in a large pedigree (Lostao MP et al 2021. PubMed ID: 34485913). Functional studies suggest that Gln457 is a critical residue within the SLC5A1 sugar-binding site and that the p.Gln457Arg substitution causes a defect in glucose transport (Loo DDF et al. 1998. PubMed ID: 9636229, Diez-Sampedro A et al. 2001. PubMed ID: 11602601; Lostao MP et al 2021. PubMed ID: 34485913). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-32495259-A-G). This variant is interpreted as pathogenic. -

Congenital glucose-galactose malabsorption Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 06, 2021

This variant is present in population databases (rs200401846, ExAC 0.02%). This sequence change replaces glutamine with arginine at codon 457 of the SLC5A1 protein (p.Gln457Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant has been observed in individual(s) with clinical features of glucose-galactose malabsorption (PMID: 9815014, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 529229). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects SLC5A1 protein function ‚Äã(PMID: 12139397, 19167319). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.87	P;.
Vest4		0.78
MutPred		0.74		Gain of phosphorylation at T460 (P = 0.2295);.;
MVP		0.97
MPC		1.4
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200401846; hg19: chr22-32495259;