Submissions for variant NM_001352754.2(ARMC9):c.1027C>A (p.Arg343Ser)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000515495	SCV004800948	uncertain significance	Joubert syndrome 30	2024-03-12	criteria provided, single submitter	curation	The heterozygous p.Arg343Ser variant in ARMC9 was identified by our study in one individual with congenital fibrosis of the extraocular muscles and Joubert syndrome, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg343Ser variant in ARMC9 has been previously reported in two siblings with Joubert syndrome 30 (PMID: 28625504) but has been identified in 0.0009% (1/113742) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs759799287). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These two affected individuals were compound heterozygotes that carried a likely pathogenic variant in trans (ClinVar Variation ID: 427933), which increases the likelihood that the p.Arg343Ser variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 427937) and has been interpreted as pathogenic by OMIM and the UW Hindbrain Malformation Research Program and as likely pathogenic by the University of Washington Center for Mendelian Genomics. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg343Cys, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 28625504, 31474318, 32552793, 35186037; Variation ID: 427932). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3, PM5_Supporting (Richards 2015).
UW Hindbrain Malformation Research Program, University of Washington	RCV000491361	SCV000579401	pathogenic	ARMC9-related Joubert syndrome	2017-05-01	no assertion criteria provided	research
OMIM	RCV000515495	SCV000611580	pathogenic	Joubert syndrome 30	2017-08-16	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV001034535	SCV001197896	likely pathogenic	Familial aplasia of the vermis		no assertion criteria provided	research

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