Submissions for variant NM_153704.6(TMEM67):c.1645C>T (p.Arg549Cys)

gnomAD frequency: 0.00003  dbSNP: rs747025617

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636959	SCV000758407	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-02-10	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 549 of the TMEM67 protein (p.Arg549Cys). This variant is present in population databases (rs747025617, gnomAD 0.02%). This missense change has been observed in individuals with Meckel syndrome (PMID: 21493627, 23351400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 530903). 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%. Experimental studies have shown that this missense change affects TMEM67 function (PMID: 26035863). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001591420	SCV001816479	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrated that mouse embryonic fibroblasts homozygous for the R549C variant failed to rescue basal responses to Wnt3a (Abdelhamed 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: 24039893, 21493627, 26035863, 26191240, 23351400, 29304564)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779030	SCV002015091	pathogenic	Joubert syndrome and related disorders	2021-10-27	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.1645C>T (p.Arg549Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251456 control chromosomes (gnomAD). This frequency is lower than the maximum expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (5.6e-05 vs 0.0018), allowing no conclusion about variant significance. c.1645C>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Joubert Syndrome and Related Disorders (Hopp_2011, Szymanska_2012, Zhang_2015), including segregation evidence in one of the reported families (Zhang_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant failed to restore the de-regulated Wnt/beta-catenin signaling in Tmem67 -/- mouse embryonic fibroblasts (Abdelhamed_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338698	SCV004047047	pathogenic	Meckel syndrome, type 3		criteria provided, single submitter	clinical testing	The missense variant p.R549C in TMEM67 (NM_153704.6) has been previously reported as homozygous or in combination with another TMEM67 variant in individuals affected with Meckel syndrome ( Hopp et al, 2011). The p.R549C variant is observed in 4/18,394 (0.0217%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Experimental studies have shown that this missense change is unable to rescue de-regulated Wnt/beta-catenin signaling that is present in a null knockout mouse model (Abdelhamed et al, 2015). There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R549C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1645 in TMEM67 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. No significant variants in gene TMEM67 were detected in the spouse.
Fulgent Genetics, Fulgent Genetics	RCV005049626	SCV005675655	likely pathogenic	COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11	2023-12-27	criteria provided, single submitter	clinical testing