Submissions for variant NM_153704.6(TMEM67):c.1844G>A (p.Cys615Tyr)

gnomAD frequency: 0.00002  dbSNP: rs377160954

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002046929	SCV002108932	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2021-04-24	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys615 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20607301, 19540516, 19508969, 26035863). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt TMEM67 protein function. This variant has not been reported in the literature in individuals with TMEM67-related conditions. This variant is present in population databases (rs377160954, ExAC 0.004%). This sequence change replaces cysteine with tyrosine at codon 615 of the TMEM67 protein (p.Cys615Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine.
PreventionGenetics, part of Exact Sciences	RCV004733388	SCV005344660	uncertain significance	TMEM67-related disorder	2024-09-20	no assertion criteria provided	clinical testing	The TMEM67 c.1844G>A variant is predicted to result in the amino acid substitution p.Cys615Tyr. To our knowledge, this variant has not been reported in the literature. Different missense variants affecting the same codon have been reported in individuals with clinical features of nephronophthisis with liver fibrosis (Otto et al. 2009. PubMed ID: 19508969; Gunay-Aygun et al. 2009. PubMed ID: 19540516; Seeman et al. 2010. PubMed ID: 20607301). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Although we suspect this variant may be pathogenic, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.