Submissions for variant NM_003611.3(OFD1):c.1030C>T (p.Arg344Ter)

gnomAD frequency: 0.00001  dbSNP: rs758903488

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001726720	SCV001961043	pathogenic	Simpson-Golabi-Behmel syndrome type 2; Joubert syndrome 10	2021-06-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471136	SCV002768363	uncertain significance	Joubert syndrome 10	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS - 3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OFD1-related disease. (I) 0109 - This gene is associated with X-linked disease. Pathogenic variants located upstream of exon 17 are typically associated with X-linked dominant orofaciodigital syndrome (OFD1) (MIM#311200), whilst variants 3' of exon 17 cause X-linked recessive Joubert syndrome (JBTS) in males (MIM#300804) (PMID: 23033313; 19800048). However, in-frame and missense variants upstream of exon 17 have been reported in male individuals affected with OFD1, suggesting that type and location of the variant may affect phenotypic outcome (PMID: 30401917; 22353940). (I) 0202 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction), but is located in an exon that may undergo alternative splicing. (SP) 0219 - This variant is non-coding in an alternative transcript. This variant in located in exon 10 of an alternative transcript, NM_001330209, which have been reported to have similar biological importance as NM_003611 (PMID: 19800048). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants reported using this transcript have very strong previous evidence for pathogenicity, however there are limited number of pathogenic variants within exon 10, an alternatively spliced exon (ClinVar). In addition, there are multiple hemizygous premature termination codon (PTC) variants reported in exon 10 in the gnomAD database, suggesting that PTCs in exon 10 are tolerated. Therefore, the biological and clinical significance of this variant is uncertain. (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been reported as a variant of unknown significance with no additional evidence (VKGL, LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (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	RCV002538677	SCV003203537	uncertain significance	Familial aplasia of the vermis; Orofaciodigital syndrome I	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg344*) in the OFD1 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs758903488, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with OFD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1298390). 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.
Revvity Omics, Revvity	RCV003130543	SCV003814261	uncertain significance	not provided	2021-08-06	criteria provided, single submitter	clinical testing
GeneDx	RCV003130543	SCV005882500	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge