Submissions for variant NM_145207.3(AFG2A):c.1A>C (p.Met1Leu)

dbSNP: rs552219028

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185657	SCV000238573	pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	Reported with a de novo missense variant on the opposite allele (in trans) in a male with features of a SPATA5-related disorder who underwent trio-based whole exome sequencing (Papuc et al., 2019); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30552426)
Invitae	RCV000652795	SCV000774666	uncertain significance	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SPATA5 mRNA. The next in-frame methionine is located at codon 75. This variant is present in population databases (rs552219028, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 30552426). ClinVar contains an entry for this variant (Variation ID: 203533). 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.
Athena Diagnostics	RCV000185657	SCV000844117	likely pathogenic	not provided	2017-12-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000185657	SCV004011559	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	AFG2A: PM2, PM3, PVS1:Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525891	SCV005039439	uncertain significance	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: SPATA5 c.1A>C (p.Met1Leu) 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. The next downstream in-frame Met is found at codon 75. No non-NMD-causing variants upstream of this codon have been classified as pathogenic. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251382 control chromosomes (gnomAD). c.1A>C has been reported in the literature in an individual affected with early-onset epileptic encephalopathy (Papuc_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30552426). ClinVar contains an entry for this variant (Variation ID: 203533). Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000652795	SCV005086726	pathogenic	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome	2023-07-17	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 neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (MIM#616577). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 27 heterozygotes, 0 homozygotes). (SP) 0311 - Multiple alternative nucleotide changes at the initiation codon are present in gnomAD (highest allele count in v2: 5 heterozygotes, 0 homozygotes). (I) 0710 - Other variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.1A>T and c.1A>G are predicted to result in a loss of the canonical translation initiation codon, and have been reported as VUS by a clinical testing laboratory in individuals without a second variant that is pathogenic, likely pathogenic or VUS in SPATA5 (ClinVar, personal communication). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as compound heterozygous in two affected individuals, one with encephalopathy and seizures, the other with clinical features including global developmental delay and hearing impairment (PMID: 30552426, DDD study). This variant has also been reported by multiple clinical testing laboratories as likely pathogenic or pathogenic (ClinVar). In addition, it has been reported as a VUS by a clinical testing laboratory in individuals without a second variant that is pathogenic, likely pathogenic or VUS in SPATA5 (ClinVar, personal communication). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000652795	SCV001745323	likely pathogenic	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome	2021-05-06	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000185657	SCV001932554	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000185657	SCV001952475	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000185657	SCV001966462	likely pathogenic	not provided		no assertion criteria provided	clinical testing