Submissions for variant NM_153704.6(TMEM67):c.638G>A (p.Arg213His)

gnomAD frequency: 0.00001  dbSNP: rs770605718

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542172	SCV000634633	pathogenic	Joubert syndrome; Meckel-Gruber syndrome	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 213 of the TMEM67 protein (p.Arg213His). This variant is present in population databases (rs770605718, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Joubert syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 461772). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMEM67 protein function. This variant disrupts the p.Arg213 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17160906, 31730820, 34032358). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002245001	SCV002512699	uncertain significance	Joubert syndrome 6	2022-01-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate, BP4 supporting
Fulgent Genetics, Fulgent Genetics	RCV002476130	SCV002791402	uncertain significance	COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11	2024-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488671	SCV004242081	uncertain significance	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.638G>A (p.Arg213His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251344 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.638G>A in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=2), or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.