Submissions for variant NM_018718.3(CEP41):c.1037A>G (p.Gln346Arg)

gnomAD frequency: 0.00002  dbSNP: rs782371437

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001051405	SCV001215558	uncertain significance	Joubert syndrome 15	2022-07-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 847788). This variant has not been reported in the literature in individuals affected with CEP41-related conditions. This variant is present in population databases (rs782371437, gnomAD 0.02%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 346 of the CEP41 protein (p.Gln346Arg).
GeneDx	RCV001772257	SCV002002361	uncertain significance	not provided	2020-07-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002553253	SCV003561036	uncertain significance	Inborn genetic diseases	2021-06-30	criteria provided, single submitter	clinical testing	The c.1037A>G (p.Q346R) alteration is located in exon 11 (coding exon 11) of the CEP41 gene. This alteration results from a A to G substitution at nucleotide position 1037, causing the glutamine (Q) at amino acid position 346 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Joe DiMaggio Children's Hospital, Memorial Healthcare System	RCV001051405	SCV001976524	pathogenic	Joubert syndrome 15		no assertion criteria provided	clinical testing	"CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium" (Lee et al. 2012). Lee et al. (2012) reported 8 patients from 3 consanguineous families with Joubert syndrome. All patients had hypotonia, ataxia, psychomotor delay with mental retardation, and the molar tooth sign on brain imaging. Additionally, "Joubert syndrome-15 is an autosomal recessive developmental disorder characterized by ataxia, hypotonia, delayed psychomotor development, and variable mental retardation. Other features, such as polydactyly, breathing abnormalities, and oculomotor apraxia, are variable" (summary by Lee et al., 2012). The c.1037A>G variant in CEP41 been observed in compound heterozygosity with c.1000G>A. As a compound heterozygote in an individual with abnormal brain MRI findings, this variant is classified as pathogenic based on functional studies.