Submissions for variant NM_016464.5(TMEM138):c.247A>G (p.Ile83Val)

gnomAD frequency: 0.00042  dbSNP: rs200399046

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000350217	SCV000341932	uncertain significance	not provided	2016-05-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000320558	SCV000372598	uncertain significance	Joubert syndrome 16	2018-01-12	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.
GeneDx	RCV000350217	SCV001780951	uncertain significance	not provided	2022-03-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22282472)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000320558	SCV002126451	uncertain significance	Joubert syndrome 16	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 83 of the TMEM138 protein (p.Ile83Val). This variant is present in population databases (rs200399046, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMEM138-related conditions. ClinVar contains an entry for this variant (Variation ID: 287964). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002521986	SCV003574077	uncertain significance	Inborn genetic diseases	2021-09-16	criteria provided, single submitter	clinical testing	The c.247A>G (p.I83V) alteration is located in exon 3 (coding exon 2) of the TMEM138 gene. This alteration results from a A to G substitution at nucleotide position 247, causing the isoleucine (I) at amino acid position 83 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV000350217	SCV005191306	uncertain significance	not provided		criteria provided, single submitter	not provided
Fulgent Genetics, Fulgent Genetics	RCV000320558	SCV005683806	uncertain significance	Joubert syndrome 16	2024-04-25	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000350217	SCV001551329	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TMEM138 p.Ile25Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs200399046) and in ClinVar (classified as a VUS by Illumina and EGL Genetic Diagnostics for Joubert Syndrome). The variant was also identified in control databases in 125 of 282888 chromosomes at a frequency of 0.000442 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 102 of 129194 chromosomes (freq: 0.00079), Other in 5 of 7226 chromosomes (freq: 0.000692), European (Finnish) in 17 of 25122 chromosomes (freq: 0.000677) and Latino in 1 of 35438 chromosomes (freq: 0.000028); it was not observed in the African, Ashkenazi Jewish, East Asian, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ile25 residue is conserved in mammals but not in more distantly related organisms however three out of four computational analyses (SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.