Submissions for variant NM_001698.3(AUH):c.381A>G (p.Ile127Met)

gnomAD frequency: 0.00125  dbSNP: rs146227896

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487826	SCV000251186	benign	not provided	2018-06-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000275240	SCV000480873	uncertain significance	3-methylglutaconic aciduria type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000487826	SCV000575581	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000275240	SCV001014469	likely benign	3-methylglutaconic aciduria type 1	2024-01-30	criteria provided, single submitter	clinical testing
Elsea Laboratory, Baylor College of Medicine	RCV000275240	SCV001424186	uncertain significance	3-methylglutaconic aciduria type 1	2020-04-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000487826	SCV001554200	likely benign	not provided		no assertion criteria provided	clinical testing	The AUH p.I127M variant was not identified in the literature but was identified in dbSNP (ID: rs146227896) and ClinVar (classified as uncertain significance by GeneDx, Illumina, CeGaT Praxis and Elsea Laboratory, Baylor College of Medicine; and as likely benign by Invitae). The variant was identified in control databases in 518 of 282744 chromosomes (5 homozygous) at a frequency of 0.001832 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I127 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) 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 (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000487826	SCV002036983	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487826	SCV002038082	uncertain significance	not provided		no assertion criteria provided	clinical testing