Submissions for variant NM_000528.4(MAN2B1):c.2867T>G (p.Leu956Arg)

gnomAD frequency: 0.00002  dbSNP: rs768233248

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV000206896	SCV002022750	likely pathogenic	Deficiency of alpha-mannosidase	2021-02-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000206896	SCV002058756	uncertain significance	Deficiency of alpha-mannosidase	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MAN2B1 related disorder (PMID:22161967, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206896	SCV003443884	uncertain significance	Deficiency of alpha-mannosidase	2022-03-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 956 of the MAN2B1 protein (p.Leu956Arg). This variant is present in population databases (rs768233248, gnomAD 0.02%). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 22161967). ClinVar contains an entry for this variant (Variation ID: 208280). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 21505070). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000206896	SCV004191855	likely pathogenic	Deficiency of alpha-mannosidase	2024-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206896	SCV005039995	likely pathogenic	Deficiency of alpha-mannosidase	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.2867T>G (p.Leu956Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251474 control chromosomes. c.2867T>G has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Riise_2012, Sandal_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating defective transport and processing (Kuokkanen_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21505070, 22161967, 33290291).ClinVar contains an entry for this variant (Variation ID: 208280). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000206896	SCV005655488	likely pathogenic	Deficiency of alpha-mannosidase	2024-03-12	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000206896	SCV000243986	uncertain significance	Deficiency of alpha-mannosidase	2012-06-07	no assertion criteria provided	literature only