ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.787G>A (p.Val263Met) (rs192838388)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185783 SCV000109862 pathogenic not provided 2012-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000185783 SCV000238719 pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing The V263M missense mutation in the ASS1 gene has been reported previously in association with citrullinemia type I (Haberle et al., 2003). Functional studies have demonstrated that this mutation is associated with some residual enzyme activity (Berning et al., 2008).
Fulgent Genetics,Fulgent Genetics RCV000078024 SCV000611161 pathogenic Citrullinemia type I 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000078024 SCV000678048 likely pathogenic Citrullinemia type I 2017-06-16 criteria provided, single submitter clinical testing V263M may be associated with a mild form of citrullinemia type 1.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000078024 SCV000732017 likely pathogenic Citrullinemia type I 2017-11-10 criteria provided, single submitter clinical testing The p.Val263Met (NM_000050.4 c.787G>A) variant in ASS1 has been reported in at l east 6 compound heterozygous and 6 homozygous individuals with mild citrullinemi a and segregated in 2 siblings from two families (Haeberle 2003 and Diez-Fernand ez 2017). Some of these individuals were asymptomatic despite having mild hyperc itrullinaemia (Haeberle 2003 and Diez-Fernandez 2017). This variant has also bee n reported in ClinVar (Variation ID#92372), as pathogenic. This variant led to r educed enzyme activity (36% as compared to wild-type) in in vitro studies (Berni ng 2008). It has been identified in 0.01% (1/10148) of Ashkenazi Jewish chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs192838388). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. In summary, although additional studies are required to fully establish it s clinical significance, the p.Val263Met variant is likely pathogenic for citr ullinemia in an autosomal recessive manner, though it is associated with a mild phenotype. ACMG/AMP Criteria applied: PM3 (upgraded to Strong based on multiple occurrences), PM2, PP5.
Invitae RCV001376591 SCV000754759 pathogenic Citrullinemia 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 263 of the ASS1 protein (p.Val263Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs192838388, ExAC 0.01%). This variant has been reported as homozygous or in combination with another ASS1 pathogenic variant in several individuals affected with mild Citrullinemia type I (MID: 14680976, 18473344, 23780642, 18925679). ClinVar contains an entry for this variant (Variation ID: 92372). Experimental studies have shown that this missense change reduces the ASS1 enzymatic activity in vitro (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000078024 SCV001163589 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000078024 SCV001338490 pathogenic Citrullinemia type I 2020-04-02 criteria provided, single submitter clinical testing Variant summary: ASS1 c.787G>A (p.Val263Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251362 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (4.8e-05 vs 0.0041), allowing no conclusion about variant significance. c.787G>A has been reported in the literature in multiple individuals in compound heterozygous or homozygous state affected with mild citrullinemia (Haberie_2003, Dimmock_2008, Barends_2014, Diez-Fernandez_2017). These data indicate that the variant is very likely to be associated with disease. At least one in vitro functional study reports this variant had an impact on protein function and results in 36% of normal activity. Six Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000078024 SCV001448988 pathogenic Citrullinemia type I 2019-09-09 criteria provided, single submitter clinical testing
GeneReviews RCV000078024 SCV000323089 pathogenic Citrullinemia type I 2016-09-01 no assertion criteria provided literature only

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