Submissions for variant NM_014846.4(WASHC5):c.210del (p.Lys70fs)

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	RCV004526423	SCV005039994	pathogenic	Ritscher-Schinzel syndrome 1	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: KIAA0196 c.210delA (p.Lys70AsnfsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250852 control chromosomes. To our knowledge, no occurrence of c.210delA in individuals affected with Ritscher-Schinzel Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004544214	SCV005040800	pathogenic	Combined oxidative phosphorylation defect type 7	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: C12orf65 c.210delA (p.Gly72AlafsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. One study of C12orf65 mRNA from a homozygous patient showed the level of the C12orf65 mRNA was not significantly reduced, suggesting that nonsense-mediated mRNA decay does not contribute to the loss of function of the C12orf65 gene product (Antonicka_2010). Truncations downstream of this position have been reported with various Mitochondrial disorders in HGMD. The variant allele was found at a frequency of 0.00018 in 251348 control chromosomes. c.210delA has been reported in the literature in multiple individuals affected mitochondrial disorders including Leigh syndrome, optic atrophy, and ophthalmoplegia (examples: Antonicka_2010, Heidary_2014, Wesolowska_2015, Schon_2021). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.