Submissions for variant NM_138425.4(C12orf57):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00003  dbSNP: rs587776954

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254835	SCV000321489	pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate expression of the c.1 A>G variant in a lentiviral construct reduces the amount of protein produced (Akizu et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28600779, 29383837, 21937992, 23453666, 27848944, 24798461, 23453665, 23633300, 28097321, 29450879, 31130284, 28454995, 33144682)
Mayo Clinic Laboratories, Mayo Clinic	RCV000034852	SCV000782492	pathogenic	Temtamy syndrome	2016-09-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000034852	SCV000807593	pathogenic	Temtamy syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in a 13-year-old female with global delays, dysmorphic features, growth failure, hypotonia, self-stimulating behaviours, and large fontanelles. Two similarly affected sisters were also homozygous for this mutation.
Invitae	RCV000034852	SCV000832479	pathogenic	Temtamy syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the C12orf57 mRNA. The next in-frame methionine is located at codon 36. This variant is present in population databases (rs587776954, gnomAD 0.007%). Disruption of the initiator codon has been observed in individuals with clinical features of Temtamy syndrome (PMID: 23453666, 23633300, 24798461, 28097321, 28454995). It is commonly reported in individuals of Middle Eastern ancestry (PMID: 28600779, 29383837). ClinVar contains an entry for this variant (Variation ID: 41942). Studies have shown that disruption of the initiator codon alters C12orf57 gene expression (PMID: 23453666). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000034852	SCV001443002	pathogenic	Temtamy syndrome	2020-06-01	criteria provided, single submitter	clinical testing	PVS1_Moderate, PS4_Supporting, PM2, PM3, PP1_Strong
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000034852	SCV002507059	likely pathogenic	Temtamy syndrome	2022-05-04	criteria provided, single submitter	curation	The homozygous p.Met1? variant in C12orf57 was identified by our study in 2 siblings with temtamy syndrome. The variant has been reported in at least 10 Arab individuals with temtamy syndrome (PMID: 23453666, 28454995, 23453665, 24798461), segregated with disease in at least 5 affected relatives from 3 families (PMID: 23453666), and has been identified in 0.006% (1/16238) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587776954). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 41942) as pathogenic by OMIM, GeneDx, Mayo Clinic Genetic Testing Laboratories, Invitae, and Baylor Genetics, and as likely pathogenic by Developmental Genetics Unit, King Faisal Specialist Hospital & Research Centre. In vitro functional studies provide some evidence that the p.Met1? variant may impact protein function (PMID: 23453666). However, these types of assays may not accurately represent biological function. The presence of this variant in at least 10 affected homozygotes, in combination with variants of uncertain significance in 2 families, and in at least 10 individuals with temtamy syndrome increases the likelihood that the p.Met1? variant is pathogenic (PMID: 23453666, 28454995, 23453665, 24798461). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_strong, PM2, PM3, PS3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034852	SCV002599008	pathogenic	Temtamy syndrome	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: C12orf57 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. At least one publication reports experimental evidence demosntarting reduced protein levels for this variant (example: Akizu_2013). One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251408 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple individuals affected with Temtamy Syndrome and/or C12orf57 related conditions (Corpus callosum hypoplasia, seizures & ocular malformations) and the variant segregated with the disease (examples: Salih_2012, Akizu_2013 and Alfares_2017). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=6) and likely pathogenic. (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000034852	SCV002820316	pathogenic	Temtamy syndrome		criteria provided, single submitter	clinical testing	The initiator codon variant p.M1V in C12orf57 (NM_138425.4) has been observed in several individuals and families affected with a neurodevelopmental disorder characterized by hypoplasia of the corpus callosum, intellectual disability and ocular defects, also known as Temtamy syndrome (Akizu N et al, Salih MA et al). Experimental studies have shown that this initiator codon change reduces C12orf57 protein expression (Akizu N et al). The variant has been reported to ClinVar as Pathogenic. The p.M1V variant is observed in 1/16,238 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.M1V variant is a loss of function variant in the gene C12orf57, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_612434.1:p.M1V and 5 others. For these reasons, this variant has been classified as Pathogenic
Revvity Omics, Revvity	RCV000034852	SCV003813063	pathogenic	Temtamy syndrome	2022-01-04	criteria provided, single submitter	clinical testing
OMIM	RCV000034852	SCV000058422	pathogenic	Temtamy syndrome	2013-06-01	no assertion criteria provided	literature only
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000162118	SCV000196403	likely pathogenic	Global developmental delay; Seizure; Abnormal corpus callosum morphology; Microphthalmia, isolated, with coloboma	2014-12-01	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000034852	SCV001433820	pathogenic	Temtamy syndrome	2019-09-15	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254835	SCV001951570	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000254835	SCV001967773	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000034852	SCV003927860	pathogenic	Temtamy syndrome	2023-04-01	no assertion criteria provided	clinical testing