Submissions for variant NM_003041.4(SLC5A2):c.1961A>G (p.Asn654Ser)

gnomAD frequency: 0.00531  dbSNP: rs61742739

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000013768	SCV001274153	uncertain significance	Familial renal glucosuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001512825	SCV001720312	benign	not provided	2023-12-15	criteria provided, single submitter	clinical testing
Mendelics	RCV002247333	SCV002519376	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000013768	SCV005400019	likely benign	Familial renal glucosuria	2020-06-11	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_003041.3(SLC5A2):c.1961A>G in exon 14 of 14 of the SLC5A2 gene. This substitution is predicted to create a minor amino acid change from asparagine to serine at position 654 of the protein, NP_003032.1(SLC5A2):p.(Asn654Ser). The asparagine at this position has moderate conservation (100 vertebrates, UCSC), but is located within the SLC5sbd_SGLT2 domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.54% (1489 heterozygotes, 10 homozygotes). The variant has been previously reported pathogenic in patients with renal glucosuria (ClinVar, Calado, J. et al. (2004)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN.
OMIM	RCV000013768	SCV000034015	pathogenic	Familial renal glucosuria	2004-02-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000013768	SCV001142463	uncertain significance	Familial renal glucosuria	2020-01-06	no assertion criteria provided	curation	NM_003041.3:c.1961A>G in the SLC5A2 gene has an allele frequency of 0.03 in Ashkenazi Jewish subpopulation in the gnomAD database. Although 10 homozygous occurrences are observed in the gnomAD database, renal glucosuria is not lethal in young age. Therefore we did not count this as a strong benign evidence. One individual with renal glucosuria, was a compound heterozygote for this variant and p.Q167fsX186 mutation (PMID: 14614622). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1; PM3.
PreventionGenetics, part of Exact Sciences	RCV003914837	SCV004734676	likely benign	SLC5A2-related disorder	2021-12-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).