Submissions for variant NM_031448.6(C19orf12):c.267del (p.Phe89fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324412	SCV004028833	pathogenic	Neurodegeneration with brain iron accumulation	2023-07-12	criteria provided, single submitter	clinical testing	Variant summary: C19orf12 c.267delT (p.Phe89LeufsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. At least one variant downstream of this position (c.371dup/p.Met124fsX17, Variation ID: 634443 in ClinVar) has been reported at a homozygous state in at-least one individual affected with autosomal recessive neurodegeneration (PMID: 23166001) and was therefore determined to be pathogenic. The current variant was absent in 250552 control chromosomes in gnomAD. Heterozygous c.267delT, described as c.300delT in NM_001031726.3, has been reported in the literature in an individual affected with features of Neurodegeneration With Brain Iron Accumulation (example: Gregory_2019). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31087512). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003984359	SCV004800529	likely pathogenic	C19orf12-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The C19orf12 c.300delT variant is predicted to result in a frameshift and premature protein termination (p.Phe100Leufs*19). This variant was reported in the heterozygous state in an individual with mitochondrial membrane protein-associated neurodegeneration (Gregory et al. 2019. PubMed ID: 31087512). This variant has not been reported in a large population database, indicating it is rare. Frameshift variants in C19orf12 are expected to be pathogenic. This variant is interpreted as likely pathogenic.