Submissions for variant NM_005262.3(GFER):c.586C>T (p.Arg196Cys)

gnomAD frequency: 0.00007  dbSNP: rs370475970

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000709773	SCV002767524	uncertain significance	Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome	2020-05-25	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_005262.2(GFER):c.586C>T in exon 3 of 3 of the GFER gene. This substitution is predicted to create a major amino acid change from an arginine to a cysteine at position 196 of the protein; NP_005253.3(GFER):p.(Arg196Cys). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the Erv1 / Alr family domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.004% (10 heterozygotes; 0 homozygotes) with a Latino sub-population frequency of 0.008%. An alternative residue change to histidine at the same location has also been reported in the gnomAD database at a frequency of 0.01%. This variant has been previously reported as pathogenic in a patient with mitochondrial disease (ClinVar, Martikainen, M. et al. (2017)). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE.
GeneDx	RCV005051785	SCV005685684	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	Identified in an individual with a mitochondrial disorder in published literature, however specific patient information was not provided (PMID: 28812649); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 28812649, 35777586)
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000508691	SCV000575906	pathogenic	Mitochondrial disease	2017-04-07	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000709773	SCV000840091	not provided	Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.