VCV000041942.42 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(17)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 41942 Accession: VCV000041942.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.31 12: 6944122 (GRCh38) [ NCBI UCSC ] 12: 7053285 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 10, 2015	Jun 17, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_138425.4:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_612434.1:p.Met1Val	missense initiator codon variant
NM_001301834.1:c.1A>G	NP_001288763.1:p.Met1Val	missense initiator codon variant
NM_001301836.2:c.14-354A>G		intron variant
NM_001301837.1:c.1A>G
NM_001301837.2:c.1A>G	NP_001288766.1:p.Met1Val	missense initiator codon variant
NM_001301838.2:c.-201A>G		5 prime UTR
NR_126035.2:n.101A>G		non-coding transcript variant
NC_000012.12:g.6944122A>G
NC_000012.11:g.7053285A>G
NG_008047.1:g.24660A>G
NG_034262.1:g.5306A>G

... more HGVS ... less HGVS

Protein change

M1V

Other names

C12ORF57, MET1VAL
NM_138425.4(C12orf57):c.1A>G
p.Met1Val

Canonical SPDI

NC_000012.12:6944121:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA130935 OMIM: 615140.0001 dbSNP: rs587776954 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
C12orf57		-	-	GRCh38 GRCh37	237	312

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Temtamy syndrome	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000034852.34
Abnormal corpus callosum morphology Global developmental delay Microphthalmia, isolated, with coloboma Seizure	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2014	RCV000162118.5
not provided	Pathogenic (4)	criteria provided, single submitter	Jan 20, 2022	RCV000254835.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temtamy syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001443002.2 First in ClinVar: Nov 14, 2020 Last updated: Sep 03, 2023	Comment: PVS1_Moderate, PS4_Supporting, PM2, PM3, PP1_Strong Clinical Features: severe ID (present) , seizures (present) , muscular hypotonia (present) , short stature (present)
Pathogenic (Sep 12, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Temtamy syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002599008.2 First in ClinVar: Nov 05, 2022 Last updated: Sep 03, 2023	Publications: PubMed (3) PubMed: 28454995‚ 23453666‚ 23633300 Comment: 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 … (more) 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. (less)
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temtamy syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807593.3 First in ClinVar: Oct 11, 2015 Last updated: Sep 03, 2023	Publications: PubMed (2) PubMed: 25326635‚ 21937992 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temtamy syndrome Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005038813.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321489.10 First in ClinVar: Oct 09, 2016 Last updated: Sep 03, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temtamy syndrome Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820316.2 First in ClinVar: Jan 21, 2023 Last updated: Sep 03, 2023	Comment: 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 … (more) 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 (less) Clinical Features: Seizure (present) , Developmental regression (present) , Global developmental delay (present) , Autism (present) , Macrocephaly (present)
Likely pathogenic (May 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Temtamy syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV002507059.2 First in ClinVar: May 16, 2022 Last updated: Sep 03, 2023	Comment: 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 … (more) 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). (less)
Pathogenic (Jan 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temtamy syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003813063.3 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Sep 12, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temtamy syndrome Affected status: unknown Allele origin: biparental	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782492.2 First in ClinVar: Oct 11, 2015 Last updated: Sep 03, 2023
Pathogenic (Dec 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Temtamy syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000832479.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 28492532‚ 23453666‚ 23633300‚ 24798461‚ 28097321‚ 28454995‚ 28600779‚ 29383837 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 20, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare Accession: SCV004175125.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Clinical Features: seizure (present) , global developmental delay (present) , abnormal facial shape (present) Age: 0-9 years Sex: male Ethnicity/Population group: South East Asian Geographic origin: Bangladesh
Likely pathogenic (Dec 01, 2014)	no assertion criteria provided (research) Method: research	Global developmental delay Epilepsy Colobomatous microphthalmia Corpus callosum abnormalities Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV000196403.2 First in ClinVar: Mar 10, 2015 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 25558065
Pathogenic (Jun 01, 2013)	no assertion criteria provided Method: literature only	TEMTAMY SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000058422.6 First in ClinVar: Apr 21, 2013 Last updated: Sep 03, 2023	Publications: PubMed (4) PubMed: 23453665‚ 23453666‚ 23633300‚ 21937992 Comment on evidence: In affected sibs, born of consanguineous Saudi Arabian parents, with mental retardation and early-onset seizures, with or without and ocular coloboma or corpus callosum abnormalities, … (more) In affected sibs, born of consanguineous Saudi Arabian parents, with mental retardation and early-onset seizures, with or without and ocular coloboma or corpus callosum abnormalities, consistent with Temtamy syndrome (TEMTYS; 218340), Zahrani et al. (2013) identified a homozygous c.1A-G transition in the C12ORF57 gene, predicted to abolish the initiating met codon and translation of the protein. The mutation was found by exome sequencing of 1 of the patients. An unrelated patient, also of Saudi Arabian descent, with a similar disorder was found to be compound heterozygous for the c.1A-G transition and a 152T-A transversion, resulting in a leu51-to-gln (L51Q; 615140.0002) substitution at a highly conserved residue. Neither mutation was found in a large exome database, 200 in-house Saudi exomes, 576 Saudi individuals, and 96 Saudi controls. In 10 patients from 4 consanguineous families of Arab descent with Temtamy syndrome, Akizu et al. (2013) identified homozygosity for the same c.1A-G mutation in C12ORF57. The mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and coincided with linkage data. All tested parents were heterozygous for the mutation, which was not found in more than 1,400 individuals, including 1,000 of Arab descent, or in public SNP databases. Haplotype analysis was consistent with a founder effect. The phenotype included hypotonia, moderate to severe intellectual disability with features of autism, corpus callosum hypoplasia or agenesis, and thalamic hypoplasia. In vitro cellular expression studies indicated that the mutation decreased protein synthesis, but some protein could be formed, likely resulting in phenotypic variability. These findings suggested a loss-of-function mechanism. In 4 sibs, born to second-cousin Saudi Arabian parents, with features of Temtamy syndrome, Salih et al. (2013) found homozygosity for the c.1A-G mutation in the C12ORF57 gene (M1V). The parents were heterozygous for the mutation, which was not found in 1 unaffected sib or in more than 350 normal individuals. Salih et al. (2013) noted that Najmabadi et al. (2011) had previously identified M1V as a possible causative mutation for nonsyndromic mental retardation in this family (G001). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951570.2 First in ClinVar: Oct 02, 2021 Last updated: Sep 03, 2023
Pathogenic (Apr 01, 2023)	no assertion criteria provided Method: clinical testing	Temtamy syndrome Affected status: yes Allele origin: germline	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) Accession: SCV003927860.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967773.2 First in ClinVar: Oct 07, 2021 Last updated: Sep 03, 2023
Pathogenic (Sep 15, 2019)	no assertion criteria provided Method: clinical testing	Temtamy syndrome Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001433820.2 First in ClinVar: Sep 27, 2020 Last updated: Sep 03, 2023	Number of individuals with the variant: 2
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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

Comment:

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).

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.	Alrakaf L	American journal of medical genetics. Part A	2018	PMID: 29383837
The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.	Monies D	Human genetics	2017	PMID: 28600779
A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield.	Alfares A	Molecular genetics and metabolism	2017	PMID: 28454995
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.	Reuter MS	JAMA psychiatry	2017	PMID: 28097321
Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures.	Platzer K	American journal of medical genetics. Part A	2014	PMID: 24798461
A newly recognized autosomal recessive syndrome affecting neurologic function and vision.	Salih MA	American journal of medical genetics. Part A	2013	PMID: 23633300
Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia.	Akizu N	American journal of human genetics	2013	PMID: 23453666
Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia.	Zahrani F	American journal of human genetics	2013	PMID: 23453665
Deep sequencing reveals 50 novel genes for recessive cognitive disorders.	Najmabadi H	Nature	2011	PMID: 21937992

Text-mined citations for rs587776954 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587776954 ...