ClinVar Miner

Submissions for variant NM_001875.5(CPS1):c.3643A>G (p.Ile1215Val)

gnomAD frequency: 0.00119  dbSNP: rs141373204
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224815 SCV000281406 uncertain significance not provided 2016-01-21 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
CeGaT Center for Human Genetics Tuebingen RCV000224815 SCV000575297 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000224815 SCV000577569 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing The I1215V variant has been reported previously in a patient with carbamoylphosphate synthetase I (CPS1) deficiency who also harbored a second variant in the CPS1 gene (Kurokawa et al. 2007). The I1215V variant is observed in 31/11564 (0.27%) alleles from individuals of Latino background, in the ExAC dataset including a homozygous individual (Lek et al., 2016). The I1215V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine and Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000986999 SCV000777135 likely benign Congenital hyperammonemia, type I 2024-01-31 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000224815 SCV000855927 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764359 SCV000895382 uncertain significance Congenital hyperammonemia, type I; Pulmonary hypertension, neonatal, susceptibility to 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000986999 SCV001136169 uncertain significance Congenital hyperammonemia, type I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000986999 SCV001298307 uncertain significance Congenital hyperammonemia, type I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab RCV000986999 SCV001737273 uncertain significance Congenital hyperammonemia, type I 2021-05-18 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV000986999 SCV001984221 uncertain significance Congenital hyperammonemia, type I 2020-05-14 criteria provided, single submitter clinical testing
New York Genome Center RCV000986999 SCV002099011 uncertain significance Congenital hyperammonemia, type I 2021-03-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844093 SCV002103655 uncertain significance not specified 2022-03-03 criteria provided, single submitter clinical testing Variant summary: CPS1 c.3643A>G (p.Ile1215Val) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251480 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency (0.0016 vs 0.0016), allowing no conclusion about variant significance. The variant allele was found at a frequency of 0.0016 in 251480 control chromosomes, predominantly at a frequency of 0.0018 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3643A>G has been reported in the literature in at-least one individual affected with Carbamoylphosphate Synthetase I Deficiency (example, Kurokawa_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Carbamoylphosphate Synthetase I Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Natera, Inc. RCV000986999 SCV001457531 likely benign Congenital hyperammonemia, type I 2020-06-16 no assertion criteria provided clinical testing

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