Submissions for variant NM_002454.3(MTRR):c.1678_1681del (p.Glu560Asnfs)

dbSNP: rs768980918

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778769	SCV000915138	pathogenic	Disorders of Intracellular Cobalamin Metabolism	2024-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824011	SCV000964886	pathogenic	Methylcobalamin deficiency type cblE	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu560Asnfs*42) in the MTRR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTRR are known to be pathogenic (PMID: 15714522). This variant is present in population databases (rs768980918, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with cobalamin E deficiency (PMID: 9501215, 25526710). This variant is also known as c.1675del4. ClinVar contains an entry for this variant (Variation ID: 631967). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001008141	SCV001167901	pathogenic	not provided	2020-01-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30041674, 25526710, 9501215)
Ambry Genetics	RCV001267450	SCV001445631	pathogenic	Inborn genetic diseases	2017-11-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465707	SCV004196479	pathogenic	Neural tube defects, folate-sensitive	2024-03-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000824011	SCV002077217	pathogenic	Methylcobalamin deficiency type cblE	2020-09-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004753037	SCV005348834	pathogenic	MTRR-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The MTRR c.1678_1681delGAGA variant is predicted to result in a frameshift and premature protein termination (p.Glu560Asnfs*42). This variant was reported along with a second likely pathogenic MTRR variant (c.166G>A, p.Val56Met) in cell lines from two siblings with cellularly confirmed homocystinuria, cblE type (described as 1675del4 in Leclerc et al 1998. PubMed ID: 9501215 and Wilson et al 1999. PubMed ID: 10484769). It was also reported along with an undocumented missense variant (c..1740C>G, p.Cys580Trp) in a patient with homocystinuria, cblE type, with a mild phenotypic presentation (Huemer M et al 2014. PubMed ID: 25526710). This variant is reported in 0.0083% of alleles in individuals of African descent in gnomAD. Frameshift variants in MTRR are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.