Submissions for variant NM_000254.2(MTR):c.3518C>T (p.Pro1173Leu) (rs121913578)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000414734	SCV000229387	pathogenic	not provided	2015-05-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210576	SCV000262940	pathogenic	Inborn genetic diseases	2015-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000414734	SCV000491199	likely pathogenic	not provided	2016-03-28	criteria provided, single submitter	clinical testing	The P1173L variant in the MTR gene has been reported in multiple individuals with a clinical diagnosis of methylcobalamin deficiency, cbIG type, reported as compound heterozygous with a second pathogenic variant (Gulati et al., 1996; Watkins et al., 2002). The P1173L variant was not observed at any increased frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1173L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P1173L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,Illumina	RCV000778974	SCV000915402	pathogenic	Disorders of Intracellular Cobalamin Metabolism	2019-01-10	criteria provided, single submitter	clinical testing	The MTR c.3518C>T (p.Pro1173Leu) is a missense variant that has been reported in at least six studies, in which it was identified in a compound heterozygous state in 14 individuals and in a homozygous state in two individuals, all diagnosed with disorders of intracellular cobalamin metabolism (Gulati et al. 1996; Gulati et al. 1997; Watkins et al. 2002; Wong et al. 2015; Alazami et al. 2015; Komulainen-Ebrahim et al. 2017). Watkins et al. (2002) performed haplotype analysis and determined that the c.3518C>T transition in a CpG island has occurred independently on at least two separate genetic backgrounds. Fibroblast cells from a female, homozygous for the p.Pro1173Leu variant and diagnosed with severe macrocytic anemia at three months, showed 9 % methionine synthase activity compared to the reference, the level of MTR protein was also reduced in these cells compared to control. The p.Pro1173Leu variant was absent from 210 control subjects and is reported at a frequency of 0.000349 in the American European population of the Exome Sequencing Project. Based on the collective evidence, the p.Pro1173Leu variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000015348	SCV000960806	pathogenic	Methylcobalamin deficiency type cblG	2019-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 1173 of the MTR protein (p.Pro1173Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs121913578, ExAC 0.009%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants or in combination with MTR variants in individuals affected with methionine synthase deficiency (cblG) (PMID: 12068375, 25526710, 9235907). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 14278). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000015348	SCV000996273	pathogenic	Methylcobalamin deficiency type cblG	2019-04-04	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and a heterozygous change in patients with methylcobalamin deficiency G (cblG) disorder (PMID: 8968736, 12068375). Functional studies of methionine synthase activity a fibroblast cell line from a patient carrying this variant showed a 30-fold reduction in enzymatic activity relative to controls, in the presence of NADPH (PMID: 9235907). It is present in the heterozygous state in the gnomAD population database at a frequency of .006% (14/243760) and thus is presumed to be rare. The c.3518C>T (p.Pro1173Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3518C>T (p.Pro1173Leu) variant is classified as pathogenic.
OMIM	RCV000015348	SCV000035607	pathogenic	Methylcobalamin deficiency type cblG	2002-07-01	no assertion criteria provided	literature only
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre	RCV000162189	SCV000196475	likely pathogenic	Intellectual disability, profound; Seizure disorder	2014-12-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003947	SCV001161937	likely pathogenic	Homocystinuria; Decreased methionine synthase activity		no assertion criteria provided	research