Submissions for variant NM_004990.4(MARS1):c.1540-3C>T

gnomAD frequency: 0.00006  dbSNP: rs372013808

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432010	SCV000525155	likely benign	not specified	2016-03-17	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230049	SCV002509807	uncertain significance	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the MARS gene. It does not directly change the encoded amino acid sequence of the MARS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs372013808, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 384378). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000432010	SCV002755147	likely benign	not specified	2020-10-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003392242	SCV004119951	uncertain significance	MARS1-related disorder	2022-12-29	criteria provided, single submitter	clinical testing	The MARS1 c.1540-3C>T variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-57905788-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.