Submissions for variant NM_032273.4(TMEM126A):c.314G>A (p.Arg105Gln)

gnomAD frequency: 0.00247  dbSNP: rs146573578

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000676594	SCV000230444	uncertain significance	not provided	2018-03-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000676594	SCV000252394	likely benign	not provided	2021-05-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000676594	SCV000891991	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TMEM126A: BP4, BS2
Invitae	RCV000676594	SCV001024594	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001114562	SCV001272462	likely benign	Autosomal recessive optic atrophy, OPA7 type	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000676594	SCV000802382	uncertain significance	not provided	2017-11-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000676594	SCV001553836	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TMEM126A p.Arg35Gln variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs146573578), ClinVar (classified as a VUS by EGL Genetics, Praxis fuer Humangenetik Tuebingen and Mayo Clinic Genetic Testing Laboratories and as likely benign by GeneDx) and LOVd 3.0. The variant was identified in control databases in 855 of 282764 chromosomes (2 homozygous) at a frequency of 0.003024 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: South Asian in 155 of 30612 chromosomes (freq: 0.005063), European (non-Finnish) in 520 of 129096 chromosomes (freq: 0.004028), Other in 23 of 7226 chromosomes (freq: 0.003183), Latino in 85 of 35430 chromosomes (freq: 0.002399), European (Finnish) in 36 of 25114 chromosomes (freq: 0.001433), African in 23 of 24966 chromosomes (freq: 0.000921), Ashkenazi Jewish in 5 of 10366 chromosomes (freq: 0.000482), and East Asian in 8 of 19954 chromosomes (freq: 0.000401). The p.Arg35 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. 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.