NM_000343.4(SLC5A1):c.1230C>G (p.Tyr410Ter) AND Congenital glucose-galactose malabsorption

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 15, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000312958.6

Allele description [Variation Report for NM_000343.4(SLC5A1):c.1230C>G (p.Tyr410Ter)]

NM_000343.4(SLC5A1):c.1230C>G (p.Tyr410Ter)

Gene:

SLC5A1:solute carrier family 5 member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.3

Genomic location:

Preferred name:

NM_000343.4(SLC5A1):c.1230C>G (p.Tyr410Ter)

HGVS:

NC_000022.11:g.32091712C>G
NG_017045.1:g.53681C>G
NM_000343.4:c.1230C>GMANE SELECT
NM_001256314.2:c.849C>G
NP_000334.1:p.Tyr410Ter
NP_001243243.1:p.Tyr283Ter
NC_000022.10:g.32487699C>G
NM_000343.3:c.1230C>G

Protein change:

Y283*

Links:

dbSNP: rs200206252

NCBI 1000 Genomes Browser:

rs200206252

Molecular consequence:

NM_000343.4:c.1230C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001256314.2:c.849C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Congenital glucose-galactose malabsorption (GGM)
Synonyms:: Glucose galactose malabsorption deficiency; Carbohydrate intolerance of glucose galactose; Complex carbohydrate intolerance; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011731; MedGen: C0268186; Orphanet: 35710; OMIM: 606824

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TI_1948077381 (0)
Nucleotide
glutamate 5-kinase [Thiocystis violascens DSM 198]
glutamate 5-kinase [Thiocystis violascens DSM 198]
gi|390427415|gnl|jgi|Thivi_2542|gb| 480.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000437934	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV004377514	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8563765, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000437934

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV004377514

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 15, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Defects in Na+/glucose cotransporter (SGLT1) trafficking and function cause glucose-galactose malabsorption.

Martín MG, Turk E, Lostao MP, Kerner C, Wright EM.

Nat Genet. 1996 Feb;12(2):216-20.

PubMed [citation]

PMID:: 8563765

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000437934.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The SLC5A1 c.1230C>G (p.Tyr410Ter) variant is a stop-gained variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Tyr410Ter variant is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this frequency is based on one allele only in a region of good sequence coverage so it is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for glucose-galactose malabsorption. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004377514.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Tyr410*) in the SLC5A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC5A1 are known to be pathogenic (PMID: 8563765). This variant is present in population databases (rs200206252, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SLC5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 341251). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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