Submissions for variant NM_001077418.3(TMEM231):c.664+4A>G

gnomAD frequency: 0.00005  dbSNP: rs760426025

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503497	SCV000597500	pathogenic	Meckel syndrome, type 11	2016-01-08	criteria provided, single submitter	clinical testing
Invitae	RCV000650603	SCV000772450	pathogenic	Joubert syndrome 20; Meckel syndrome, type 11	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the TMEM231 gene. It does not directly change the encoded amino acid sequence of the TMEM231 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs760426025, gnomAD 0.02%). This variant has been observed in individual(s) with Meckel syndrome (PMID: 25869670). 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: 437009). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 25869670). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003129877	SCV003814082	likely pathogenic	not provided	2022-08-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492085	SCV004241099	pathogenic	Joubert syndrome and related disorders	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: TMEM231 c.823+4A>G, also referred to as c.664+4A>G, alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in a frameshift leading to a premature truncation that is expected to undergo nonsense mediated decay (Roberson_2015). The variant allele was found at a frequency of 6.8e-05 in 249240 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TMEM231 causing Joubert Syndrome And Related Disorders (6.8e-05 vs 0.0004), allowing no conclusion about variant significance. c.823+4A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Meckel Syndrome from several different families (Roberson_2015). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 25869670). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.