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

gnomAD frequency: 0.00243  dbSNP: rs115923556

Total submissions: 9

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.
Eurofins Ntd Llc (ga)	RCV000223962	SCV000331463	uncertain significance	not provided	2015-07-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000223962	SCV000641776	likely benign	not provided	2024-01-31	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 Laboratory Services, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000223962	SCV002542169	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003929925	SCV004746084	likely benign	MMUT-related disorder	2020-05-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.