Submissions for variant NM_152269.5(MTRFR):c.96_99dup (p.Pro34fs)

gnomAD frequency: 0.00006  dbSNP: rs863223926

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198209	SCV000251228	pathogenic	not provided	2018-11-29	criteria provided, single submitter	clinical testing	The c.96_99dupATCC variant in the C12orf65 gene has been reported previously in association with optic atrophy and respiratory chain defects in several unrelated individuals who were homozygous for c.96_99dupATCC or compound heterozygous for c.96_99dupATCC and another frame shift variant in C12orf65 (Taylor et al., 2014; Heidary et al., 2014; Pyle et al., 2014). The duplication causes a frameshift starting with codon Proline 34, changes this amino acid to a Isoleucine residue and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Pro34IlefsX25. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694009	SCV000822434	pathogenic	Combined oxidative phosphorylation defect type 7; Spastic paraplegia	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro34Ilefs*25) in the C12orf65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C12orf65 are known to be pathogenic (PMID: 20598281, 24424123). This variant is present in population databases (rs765675424, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Behr’s syndrome (PMID: 24284555, 25058219, 26380172, 28251916). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214192). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000198209	SCV001248119	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500608	SCV002810304	pathogenic	Combined oxidative phosphorylation defect type 7; Hereditary spastic paraplegia 55	2022-03-30	criteria provided, single submitter	clinical testing