Submissions for variant NM_001077418.3(TMEM231):c.664G>A (p.Val222Ile)

gnomAD frequency: 0.00005  dbSNP: rs397514753

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000054806	SCV001521033	pathogenic	Meckel syndrome, type 11	2020-01-14	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV001781386	SCV002016901	likely pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing
Invitae	RCV003764728	SCV004570099	pathogenic	Joubert syndrome 20; Meckel syndrome, type 11	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 275 of the TMEM231 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TMEM231 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs397514753, gnomAD 0.01%). This variant has been observed in individual(s) with Meckel syndromes (PMID: 23349226, 25869670). ClinVar contains an entry for this variant (Variation ID: 64619). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 23349226). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003915018	SCV004737036	likely pathogenic	TMEM231-related condition	2024-02-19	criteria provided, single submitter	clinical testing	The TMEM231 c.823G>A variant is predicted to result in the amino acid substitution p.Val275Ile. This variant, reported as c.751G>A, was reported in the homozygous state in a fetus with Meckel-Gruber syndrome (Shaheen et al. 2013. PubMed ID: 23349226). The c.823G>A is the terminal nucleotide of exon 4 adjacent to the GT donor site. Functional studies found that this variant interferes with normal splicing (Shaheen et al. 2013. PubMed ID: 23349226; Maddirevula et al. 2020. PubMed ID: 32552793, Table S1). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003987343	SCV004805175	pathogenic	Joubert syndrome 20	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000054806	SCV000083051	pathogenic	Meckel syndrome, type 11	2013-03-01	no assertion criteria provided	literature only
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000162154	SCV000196440	likely pathogenic	Meckel-Gruber syndrome	2014-12-01	no assertion criteria provided	research