Submissions for variant NM_153704.6(TMEM67):c.1321C>T (p.Arg441Cys)

gnomAD frequency: 0.00002  dbSNP: rs752362727

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201784	SCV000256517	pathogenic	Joubert syndrome 6	2015-02-23	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414925	SCV000493010	likely pathogenic	Familial aplasia of the vermis; Oligohydramnios; Renal cyst	2014-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623940	SCV000741568	likely pathogenic	Inborn genetic diseases	2016-06-07	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000627003	SCV000747706	likely pathogenic	Congenital ocular coloboma; Global developmental delay; Visual impairment; Nystagmus; Absent speech; Barrel-shaped chest; Kidney damage; Cerebellar vermis hypoplasia; Tremor; Pancreatitis; Cerebellar malformation; Peritonitis; Infantile muscular hypotonia; Intellectual disability, severe	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763609	SCV000894455	pathogenic	COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; Bardet-Biedl syndrome 14; Nephronophthisis 11	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853244	SCV002243654	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 441 of the TMEM67 protein (p.Arg441Cys). This variant is present in population databases (rs752362727, gnomAD 0.006%). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 23351400). ClinVar contains an entry for this variant (Variation ID: 217725). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg441 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 20232449), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV003997037	SCV004847172	uncertain significance	Meckel syndrome, type 3	2021-11-18	criteria provided, single submitter	clinical testing