Submissions for variant NM_001077418.3(TMEM231):c.625G>A (p.Asp209Asn)

gnomAD frequency: 0.00004  dbSNP: rs200799769

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255979	SCV000322102	likely pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23012439, 27449316, 26477546)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543480	SCV000652865	pathogenic	Joubert syndrome 20; Meckel syndrome, type 11	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 262 of the TMEM231 protein (p.Asp262Asn). This variant is present in population databases (rs200799769, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 23012439, 27449316). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Asp209Asn. ClinVar contains an entry for this variant (Variation ID: 39822). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000255979	SCV000855454	pathogenic	not provided	2017-07-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513311	SCV003753180	uncertain significance	Inborn genetic diseases	2022-06-16	criteria provided, single submitter	clinical testing	The c.712G>A (p.D238N) alteration is located in exon 4 (coding exon 4) of the TMEM231 gene. This alteration results from a G to A substitution at nucleotide position 712, causing the aspartic acid (D) at amino acid position 238 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155046	SCV003844339	pathogenic	Joubert syndrome and related disorders	2023-02-01	criteria provided, single submitter	clinical testing	Variant summary: TMEM231 c.784G>A (p.Asp262Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249258 control chromosomes. This frequency is not significantly higher than expected 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.784G>A has been reported in the literature in multiple individuals affected with Joubert Syndrome And Related Disorders (e.g., Srour_2012, Maglic_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000033042	SCV000056822	pathogenic	Joubert syndrome 20	2012-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004755755	SCV005344586	pathogenic	TMEM231-related disorder	2024-03-19	no assertion criteria provided	clinical testing	The TMEM231 c.784G>A variant is predicted to result in the amino acid substitution p.Asp262Asn. This variant can also be referred to as (NM_001077418.1:c.625G>A (p.Asp209Asn). This variant, along with a protein truncating variant has been previously identified in three individuals with Joubert syndrome (JS) from two different families (Srour et al. 2012. PubMed ID: 23012439). Also, this variant along with an exonic deletion has been reported in three affected individuals with JS (Maglic et al. 2016. PubMed ID: 27449316). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.