ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.205A>G (p.Ile69Val) (rs115923556)

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Total submissions: 7
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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 RCV000223962 SCV000280772 uncertain significance not provided 2015-02-03 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000223962 SCV000331463 uncertain significance not provided 2015-07-08 criteria provided, single submitter clinical testing
Invitae RCV000223962 SCV000641776 likely benign not provided 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000223962 SCV000978066 likely benign not provided 2018-05-25 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.
Illumina Clinical Services Laboratory,Illumina RCV001085527 SCV001322760 uncertain significance Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 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.
Natera, Inc. RCV001271806 SCV001453246 benign Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency 2019-12-31 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000223962 SCV001553351 uncertain significance not provided no assertion criteria provided clinical testing The MUT p.Ile69Val variant was identified in dbSNP (ID: rs115923556), LOVD 3.0, ClinVar (classified as likely benign by Invitae and as a VUS by EGL Genetics and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and Cosmic (FATHMM predicted pathogenic; score=0.91). The variant was also identified in control databases in 602 of 282866 chromosomes (2 homozygous) at a frequency of 0.002128 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 458 of 129172 chromosomes (freq: 0.003546), European (Finnish) in 85 of 25120 chromosomes (freq: 0.003384), Other in 15 of 7228 chromosomes (freq: 0.002075), African in 14 of 24968 chromosomes (freq: 0.000561), South Asian in 16 of 30616 chromosomes (freq: 0.000523) and Latino in 14 of 35440 chromosomes (freq: 0.000395), while the variant was not observed in the Ashkenazi Jewish and East Asian populations. The I69V variant was identified in 1/25 patients with isolated methylmalonic acidemia (freq=0.02) but was suggested to be a polymorphism (Martinez_2005_PMID:15781192). This variant was also identified in the heterozygous state in 1/160 cell lines from patients with the mitochondrial enzyme methylmalonyl CoA mutase (MCM) deficiency (freq=0.003) but was also suggested to be a polymorphism (Worgan_2006_PMID:16281286). The p.Ile69 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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