Submissions for variant NM_153704.6(TMEM67):c.1078A>G (p.Thr360Ala)

gnomAD frequency: 0.00188  dbSNP: rs140191346

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174181	SCV000225439	likely benign	not specified	2015-05-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000988094	SCV001137676	benign	Joubert syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001409831	SCV001611864	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001356583	SCV001767688	uncertain significance	not provided	2021-12-08	criteria provided, single submitter	clinical testing	Reported in an individual with a ciliopathy who harbored an additional likely benign variant on the opposite TMEM67 allele (Consugar et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25412400)
Mayo Clinic Laboratories, Mayo Clinic	RCV001356583	SCV004224199	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975266	SCV004800611	likely benign	TMEM67-related condition	2020-02-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356583	SCV001551794	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TMEM67 p.Thr360Ala variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs140191346), ClinVar (classified as likely benign by EGL Genetics) and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 147 of 282650 chromosomes at a frequency of 0.00052 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 142 of 24952 chromosomes (freq: 0.005691), Other in 1 of 7214 chromosomes (freq: 0.000139), South Asian in 2 of 30598 chromosomes (freq: 0.000065) and Latino in 2 of 35432 chromosomes (freq: 0.000056); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and European (non-Finnish) 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.Thr360 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.