Submissions for variant NM_004990.4(MARS1):c.2204+11G>A

gnomAD frequency: 0.00226  dbSNP: rs202080192

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427227	SCV000521871	likely benign	not specified	2017-12-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174280	SCV001337410	benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230250	SCV002509678	benign	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U	2025-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001702451	SCV004564714	benign	not provided	2024-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427227	SCV006070807	benign	not specified	2025-03-03	criteria provided, single submitter	clinical testing	Variant summary: MARS1 c.2204+11G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0037 in 1614082 control chromosomes in the gnomAD database, including 22 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in MARS1 causing Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency phenotype (0.0011). To our knowledge, no occurrence of c.2204+11G>A in individuals affected with Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 382084). Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000427227	SCV001921071	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702451	SCV001931006	likely benign	not provided		no assertion criteria provided	clinical testing