ClinVar Miner

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

gnomAD frequency: 0.00188  dbSNP: rs140191346
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Total submissions: 5
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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 Joubert syndrome; Meckel-Gruber syndrome 2021-11-26 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)
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.

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