Submissions for variant NM_003051.4(SLC16A1):c.1117G>A (p.Val373Ile)

gnomAD frequency: 0.00003  dbSNP: rs200802632

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000259519	SCV000347269	uncertain significance	Exercise-induced hyperinsulinism	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000994073	SCV001147379	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000994073	SCV003251479	uncertain significance	not provided	2023-05-22	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 291859). This variant has not been reported in the literature in individuals affected with SLC16A1-related conditions. This variant is present in population databases (rs200802632, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 373 of the SLC16A1 protein (p.Val373Ile).
Ambry Genetics	RCV002519370	SCV003603678	uncertain significance	Inborn genetic diseases	2022-07-08	criteria provided, single submitter	clinical testing	The c.1117G>A (p.V373I) alteration is located in exon 4 (coding exon 3) of the SLC16A1 gene. This alteration results from a G to A substitution at nucleotide position 1117, causing the valine (V) at amino acid position 373 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV003151012	SCV003840054	uncertain significance	not specified	2022-07-23	no assertion criteria provided	clinical testing	DNA sequence analysis of the SLC16A1 gene demonstrated a sequence change, c.1117G>A, in exon 4 that results in an amino acid change, p.Val373Ile. This sequence change does not appear to have been previously described in individuals with SLC16A1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.009% in the Ashkenazi Jewish subpopulation (dbSNP rs200802632). The p.Val373Ile change affects a moderately conserved amino acid residue located in a domain of the SLC16A1 protein that is known to be functional. The p.Val373Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val373Ile change remains unknown at this time. Heterozygous pathogenic variants in SLC16A1 have been associated with familial hyperinsulinemic hypoglycemia type 7 [OMIM# 610021]. All pathogenic variants described in this gene associated with hyperinsulinism to date have been located within the promotor region in individuals with exercise-induced hyperinsulinemic hypoglycemia (Otonkoski et al, 2007. Am. J. Hum. Genet. 81: 467-74). Two missense variants have been described in individuals with congenital hyperinsulinism (PMID: 33502730, 28491926). Pathogenic variants in SLC16A1 have also been associated with autosomal dominant and autosomal recessive monocarboxylate transporter 1 deficiency [OMIM# 616095] characterized by ketoacidosis and ketotic hypoglycemia, and autosomal dominant erythrocyte lactate transporter defect [OMIM# 245340] characterized by exercise-induced muscle cramping and fatigue.