Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169614 | SCV000221140 | likely pathogenic | beta Thalassemia | 2015-02-17 | criteria provided, single submitter | literature only | |
| ARUP Laboratories, |
RCV003476897 | SCV000885556 | pathogenic | not provided | 2023-03-06 | criteria provided, single submitter | clinical testing | The Hb San Diego variant (HBB: c.328G>A; p.Val110Met, also known as Val109Met when numbered from the mature protein, rs33969677) has been reported in a heterozygous state in multiple individuals with familial erythrocytosis (Bento 2013, Gonzalez Fernandez 2009, Nute 1974, HbVar database and references therein). It is listed in ClinVar (Variation ID: 15342), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The residue Val110 is within the alpha1beta2 contact zone, which is important for oxygen uptake and its related allosteric effects (Gonzalez Fernandez 2009). The valine at codon 110 is moderately conserved, and functional characterization of the variant hemoglobin demonstrates increased oxygen affinity (reduced P50), resulting in reduced oxygen release to the tissue (Chanarin 1975, Nute 1974). In addition, this variant has been shown to segregate with increased oxygen affinity (Nute 1974). An additional high oxygen affinity Hb variant at this position (Hb Johnstown: Val110Leu) has also been described in association with erythrocytosis (Feliu-Torres 2004). Based on available information, the Hb San Diego variant is considered pathogenic for familial erythrocytosis. REFERENCES Link to HbVar database for Hb San Diego: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=483 Bento C et al. Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?). Eur J Haematol. 2013; 91(4):361-8. Chanarin I et al. Erythraemia due to haemoglobin San Diego. Br J Haematol. 1975; 30(2):167-75. Feliu-Torres A et al. Hb Johnstown (beta109(G11)Val-->Leu): A high oxygen affinity variant associated with beta0-thalassemia. Hemoglobin. 2004;28(4):335-8. Gonzalez Fernandez F et al. Haemoglobinopathies with high oxygen affinity. Experience of Erythropathology Cooperative Spanish Group. Ann Hematol. 2009; 88(3):235-8. Nute P et al. Hemoglobinopathic erythrocytosis due to a new electrophoretically silent variant, hemoglobin San Diego (beta109 (G11)val--met). J Clin Invest. 1974;53(1):320-8. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001553627 | SCV001774559 | pathogenic | Hemoglobinopathy | 2021-07-16 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.328G>A (p.Val110Met), also known as Hb San Diego, results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251212 control chromosomes. c.328G>A has been reported in the literature in multiple individuals and families affected with idopathic or familial erythrocytosis (Nute_1974, Rumi_2008, Bento_2013, Boster_2019, Camps_2016, Gonzalez Fernandez_2009, Xiong_2019). Additionally, the variant was reported to co-segregate with erythrocytosis in two- and three-generation families in an autosomal dominant manner (Gonzalez Fernandez_2009, Xiong_2019). These data indicate that the variant is very likely to be associated with familial erythrocytosis. P50 values were shown to be reduced in affected indviduals and family members (Nute_1974, Rumi_2008). 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/likely pathogenic. To our knowledge, Hb San Diego has not been reported in the homozygous state, in combination with beta thalassemia or other beta globin variants, therefore its pathogenicity in regards to beta thalassemia is unknown. Based on the evidence outlined above, the variant was classified as pathogenic for erythrocytosis. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003476897 | SCV004219882 | pathogenic | not provided | 2022-09-26 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals and families affected with erythrocytosis (PMIDs: 1201208 (1975), 7204093 (1981), 6863429 (1983), 18818920 (2009), 23859443 (2013), and 27651169 (2016). This variant has also been shown to co-segregate with erythrocytosis (PMIDs: 18793248 (2009), 30423154 (2019), and 31304856 (2019)). This variant has also been shown to co-segregate with erythrocytosis (PMIDs: 18793248 (2009) and 30423154 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic. |
| OMIM | RCV000016585 | SCV000036854 | other | HEMOGLOBIN SAN DIEGO | 2017-12-12 | no assertion criteria provided | literature only | |
| OMIM | RCV000641606 | SCV000763248 | pathogenic | Erythrocytosis, familial, 6 | 1995-01-01 | no assertion criteria provided | literature only |