ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.556C>A (p.Arg186=) (rs111407265)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000123693 SCV000167036 benign not specified 2014-04-04 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000123693 SCV000336951 benign not specified 2015-11-06 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000425778 SCV000510793 likely benign not provided 2017-01-24 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Invitae RCV001084648 SCV000756213 benign Argininosuccinate lyase deficiency 2020-12-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123693 SCV000918493 benign not specified 2018-06-25 criteria provided, single submitter clinical testing Variant summary: ASL c.556C>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational 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 0.0014 in 247432 control chromosomes, predominantly at a frequency of 0.012 within the African subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ASL causing Argininosuccinic Aciduria phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.556C>A in individuals affected with Argininosuccinic Aciduria and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.

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