Submissions for variant NM_001377295.2(GNAT2):c.937C>T (p.Arg313Ter)

gnomAD frequency: 0.00001  dbSNP: rs748981899

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000761410	SCV002557753	pathogenic	Achromatopsia 4	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with achromatopsia 4 (MIM#613856). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0601 - Variant results in the loss of the well-established functional GTP binding domain, conserved motif and GTP, Mg2+ and receptor-binding residues (NCBI domains, PMID: 31058429, PMID: 18643908). (I) 0704 - Other protein truncation variants comparable to the one identified in this case has limited previous evidence for pathogenicity. One variant, p.(Ile319fs*5), has been reported as pathogenic and observed in compound heterozygous siblings with achromatopsia (PMID: 31058429, ClinVar). p.(Tyr320*) has been reported as pathogenic (LOVD). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and observed in two unrelated homozygous individuals with congenital achromatopsia or cone dystrophy, and a compound heterozygous individual with achromatopsia (ClinVar, PMID: 21107338, PMID: 27208204, PMID: 31058429). (SP) 0906 - Segregation evidence for this variant is inconclusive. Segregation testing demonstrated that all affected individuals in a large family shared the same homozygous haplotype, whereas unaffected relatives did not. These findings were considered inconclusive (PMID: 21107338). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558561	SCV004291968	pathogenic	not provided	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg313*) in the GNAT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the GNAT2 protein. This variant is present in population databases (rs748981899, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 21107338). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 623285). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000761410	SCV000891394	likely pathogenic	Achromatopsia 4	2018-06-12	no assertion criteria provided	research