Submissions for variant NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter)

dbSNP: rs775200333

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723878	SCV000331576	pathogenic	not provided	2015-12-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000301281	SCV000410795	pathogenic	Deficiency of alpha-mannosidase	2017-04-28	criteria provided, single submitter	clinical testing	The MAN2B1 c.1383C>A (p.Tyr461Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in a total of eight individuals with alpha-mannosidosis (including two sibling pairs) in a compound heterozygous state (Stensland et al 2012; Borgwardt et al. 2015). Control data are not available for this variant, which is reported at a frequency of 0.0001525 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele only in a region of poor sequence coverage. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Tyr461Ter variant is classified as pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000301281	SCV001468285	pathogenic	Deficiency of alpha-mannosidase	2020-12-25	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.1383C>A (p.Tyr461X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.7e-05 in 172302 control chromosomes. c.1383C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis and subsequently cited by others (example, Riise Stensland_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. One submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000723878	SCV001781059	pathogenic	not provided	2020-12-07	criteria provided, single submitter	clinical testing	Nonsense 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: 26048034, 22161967, 17979865)
Genome-Nilou Lab	RCV000301281	SCV002014364	pathogenic	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV000301281	SCV002246670	pathogenic	Deficiency of alpha-mannosidase	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr461*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with alpha-mannosidosis (PMID: 22161967). ClinVar contains an entry for this variant (Variation ID: 281152). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000301281	SCV002503619	pathogenic	Deficiency of alpha-mannosidase	2021-04-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 461 in exon 11 (of 24) of MAN2B1 (p.(Tyr461*)). It is expected to result in nonsense mediated decay, in a gene where loss of function is an established mechanism of disease (ClinGen). The variant is present in a large population cohort at a frequency of 0.002% (3/172,302 alleles, 0 homozygotes in gnomAD v2.1), but this is based on three alleles in a region of poor coverage. It has been reported in multiple individuals with alpha-mannosidosis with a second pathogenic allele, and segregates with the condition in at least one family (PMID: 22161967, 26048034). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC . Following criteria are met: PVS1, PM3_Strong, PP1.
Baylor Genetics	RCV000301281	SCV004191898	pathogenic	Deficiency of alpha-mannosidase	2023-03-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000301281	SCV002086932	pathogenic	Deficiency of alpha-mannosidase	2020-05-08	no assertion criteria provided	clinical testing