Submissions for variant NM_000254.3(MTR):c.3079C>T (p.Arg1027Trp)

gnomAD frequency: 0.00235  dbSNP: rs116836001

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766292	SCV000239003	uncertain significance	not provided	2018-04-16	criteria provided, single submitter	clinical testing	p.Arg1027Trp (CGG>TGG): c.3079 C>T in exon 29 in the MTR gene (NM_000254.2). The R1027W variant in the MTR gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Sequencing Project reports R1027W was observed in 33/8600 alleles (0.38%) from individuals of European American background; however, this variant was not observed in the homozygous state in any individual within this population. The R1027W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1027W as a variant of unknown significance. This variant has been observed to be maternally and paternally inherited. The variant is found in the MTR panel.
Illumina Laboratory Services, Illumina	RCV000314594	SCV000356047	likely benign	Disorders of Intracellular Cobalamin Metabolism	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000766292	SCV000604297	uncertain significance	not provided	2019-11-03	criteria provided, single submitter	clinical testing	The MTR c.3079C>T, p.Arg1027Trp variant (rs116836001), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 203839). This variant is found in the general population with an allele frequency of 0.28% (811/282,858 alleles, including 6 homozygotes) in the Genome Aggregation Database. The arginine at codon 1027 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time.
Invitae	RCV001080972	SCV001115736	benign	Methylcobalamin deficiency type cblG	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766292	SCV004009948	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MTR: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003927726	SCV004742065	likely benign	MTR-related disorder	2024-02-15	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).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766292	SCV001978147	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766292	SCV001980285	likely benign	not provided		no assertion criteria provided	clinical testing