B2M

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009434

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0971010

Submitter: ClinGen

The *B2M* gene is located on chromosome 15 at 15q21.1 and encodes beta-2-microglobulin, a serum protein found in association with the major histocompatibility complex class I heavy chain on the surface of nearly all nucleated cells. The protein has a predominantly beta-pleated sheet structure that can form amyloid fibrils in some pathological conditions. *B2M* was first reported in relation to autosomal dominant hereditary systemic amyloidosis 6 in 2012 (Valleix et al., PMID: 22693999). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into two disease entities: hypercatabolic hypoproteinemia (OMIM:241600) and hereditary systemic amyloidosis 6 (OMIM:620659). The split curation for autosomal recessive hypercatabolic hypoproteinemia has been curated separately. Two missense variants that have been reported in two probands in two publications (PMIDs: 22693999, 35575118) are included in this curation. The mechanism of pathogenicity appears to be gain of function. This gene-disease relationship is also supported by variant-level evidence showing that D76N *B2M* results in increased abundance compared to wild type of an intermediate of the *B2M* folding pathway that plays a role in priming the amyloid transition (PMID:24014031). No experimental evidence was scored. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date May 6, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0007099

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009434

Submitter: ClinGen

*B2M* was first reported in relation to B2M deficiency, initially referred to as autosomal recessive familial hypercatabolic hypoproteinemia (FHH) in 2006 (Wani et al., PMID: 16549777). B2M deficiency is characterized by hypoproteinemia, hypogammaglobulinemia, decreased immune cells (B cells, NK cells, and alpha-beta T cells), abnormal skin lesions including granulomatous dermatitis and ulcerations, bronchiectasis, and limb anomalies. The mechanism of pathogenicity appears to be homozygous loss of function. The curation of *B2M* related to B2M deficiency includes both case-level and experimental evidence. Two variants (missense and splice site) have been reported two probands in two publications (PMID: 16549777, 25702838) are included in this curation. Heterozygous carriers were not identified to have any clinical features associated with B2M deficiency. This gene-disease relationship is also supported by recapitulation of decreased T cells and absent cell surface expression of MHC-1 in a *B2M*-null mouse model (PMID: 2112266), lack of expression of the B2M protein along with other MHC-I proteins including neonatal Fc receptor (FcRn) protein in patient derived cells (PMID: 25702838), and the reduced full length mRNA expression using RT-PCR in an individual with confirmed canonical splice site mutation and B2M deficiency in serum (PMID: 25702838). These results support the role of *B2M* in the development and function of major histocompatibility complex-I (MHC-I), an important component of the immune response system. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Of note, this gene has also been implicated in autosomal dominant familial visceral amyloidosis. At this time, there has only been a single published report of a variant in *B2M* in an individual with amyloidosis (PMID: 22693999). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in the reported mechanism, inheritance, and phenotype of the reported individual with amyloidosis and those reported with B2M deficiency. However, more information is needed regarding these two conditions to assess if they should be lumped or split. At the time of this curation, these disease entities will be treated as split, and only B2M deficiency will be assessed. This classification was approved by the ClinGen SCID/CID Gene Curation Expert Panel on the meeting date 3/21/2021 (SOP Version [10]).

Inheritance Pattern: AD

Disease ID:MONDO:0017810

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0017810

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009434

Submitter: PanelApp Australia