Submissions for variant NM_012434.5(SLC17A5):c.500T>C (p.Leu167Pro)

gnomAD frequency: 0.00001  dbSNP: rs587779410

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622448	SCV000741968	uncertain significance	Inborn genetic diseases	2016-11-10	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001271946	SCV001480291	uncertain significance	Salla disease	2019-10-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731374	SCV001983635	uncertain significance	not specified	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: SLC17A5 c.500T>C (p.Leu167Pro) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.500T>C has been reported in the literature as a compound heterozygous genotype in at-least one comprehensively evaluated and biochemically diagnosed individual affected with Sialic Acid Storage Disorder (example, Couce_2014, Fernandez-Marmiesse_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001271946	SCV002027590	uncertain significance	Salla disease	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477258	SCV002785597	uncertain significance	Sialic acid storage disease, severe infantile type; Salla disease	2021-10-22	criteria provided, single submitter	clinical testing
Invitae	RCV001271946	SCV003439498	likely pathogenic	Salla disease	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 167 of the SLC17A5 protein (p.Leu167Pro). This variant is present in population databases (rs587779410, gnomAD 0.006%). This missense change has been observed in individual(s) with sialic acid storage disorders (PMID: 24993898). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 100735). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC17A5 protein function with a positive predictive value of 80%. 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.
Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. Hospital Clínico Universitário de Santiago de Compostela	RCV000087101	SCV000119958	pathogenic	Sialic acid storage disease, severe infantile type		no assertion criteria provided	research
Natera, Inc.	RCV001271946	SCV001453514	uncertain significance	Salla disease	2020-09-16	no assertion criteria provided	clinical testing