Submissions for variant NM_002454.3(MTRR):c.903+469T>C

gnomAD frequency: 0.00007  dbSNP: rs893229476

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820217	SCV000960921	pathogenic	Methylcobalamin deficiency type cblE	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the MTRR gene. It does not directly change the encoded amino acid sequence of the MTRR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individuals with homocystinuria due to cobalamin E deficiency (PMID: 10484769, 12555939, 15714522). This variant is also known as c.903-904ins140. ClinVar contains an entry for this variant (Variation ID: 662553). Studies have shown that this variant results in insertion of 140 nucleotides and introduces a premature termination codon (PMID: 12555939, 20120036). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000820217	SCV001136811	pathogenic	Methylcobalamin deficiency type cblE	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001532026	SCV001747403	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MTRR: PM3:Very Strong, PM2, PP4:Moderate, PS3:Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000820217	SCV004029422	pathogenic	Methylcobalamin deficiency type cblE	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: MTRR c.903+469T>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing at the specific intronic location, however, at-least one publication reports experimental evidence that this variant affects mRNA splicing resulting in a pseudoexon inclusion attributed to the creation of an exonic splicing enhancer (Homolova_2010). The variant allele was found at a frequency of 9.6e-05 in 31400 control chromosomes. c.903+469T>C is the most frequent mutation causing the cblE type of homocystinuria and has been reported in the literature in individuals affected with Homocystinuria-Megaloblastic Anemia, cbl E type (example, Wilson_1999, Zavadakova_2002, Lotz-Havla_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20120036, 33980297, 10484769, 15714522, 12555939). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003467497	SCV004196487	pathogenic	Neural tube defects, folate-sensitive	2023-09-26	criteria provided, single submitter	clinical testing
OMIM	RCV000820217	SCV000027648	pathogenic	Methylcobalamin deficiency type cblE	2002-10-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000820217	SCV002077201	pathogenic	Methylcobalamin deficiency type cblE	2020-11-17	no assertion criteria provided	clinical testing
GeneReviews	RCV002537460	SCV003354482	not provided	Disorders of Intracellular Cobalamin Metabolism		no assertion provided	literature only