Submissions for variant NM_001044385.3(TMEM237):c.439G>A (p.Val147Ile)

gnomAD frequency: 0.00026  dbSNP: rs200531617

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000287196	SCV000340013	uncertain significance	not provided	2016-03-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001048032	SCV000426242	uncertain significance	Joubert syndrome 14	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.
Invitae	RCV001048032	SCV001212021	uncertain significance	Joubert syndrome 14	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 147 of the TMEM237 protein (p.Val147Ile). This variant is present in population databases (rs200531617, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TMEM237-related conditions. ClinVar contains an entry for this variant (Variation ID: 286536). 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 not expected to disrupt TMEM237 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	RCV002519236	SCV003739243	uncertain significance	Inborn genetic diseases	2021-08-30	criteria provided, single submitter	clinical testing	The c.439G>A (p.V147I) alteration is located in exon 7 (coding exon 7) of the TMEM237 gene. This alteration results from a G to A substitution at nucleotide position 439, causing the valine (V) at amino acid position 147 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.