ClinVar Miner

Submissions for variant NM_001077418.3(TMEM231):c.625G>A (p.Asp209Asn) (rs200799769)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255979 SCV000322102 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM231 gene. The D262N variant has been observed with a pathogenic variant on the opposite allele (in trans) in unrelated patients referred for genetic testing at GeneDx and in the published literature (Maglic et al., 2016). This variant is observed in 16/126,692 (0.013%) alleles from individuals of European background (Lek et al., 2016). The D262N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether the D262N variant is a pathogenic variant or a rare benign variant.
Invitae RCV000543480 SCV000652865 pathogenic Joubert syndrome 20; Meckel syndrome, type 11 2020-01-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 262 of the TMEM231 protein (p.Asp262Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs200799769, ExAC 0.01%). This variant has been reported to segregate with Joubert syndrome in multiple families (PMID: 23012439, 27449316). This variant is also known as Asp209Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 39822). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255979 SCV000855454 pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing
OMIM RCV000033042 SCV000056822 pathogenic Joubert syndrome 20 2012-10-01 no assertion criteria provided literature only

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