ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.328G>A (p.Val110Met) (rs33969677)

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Total submissions: 5
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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, Molecular Genetics and Genomics,ARUP Laboratories RCV000757363 SCV000885556 pathogenic not specified 2019-03-19 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, LabCorp 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.
OMIM RCV000016585 SCV000036854 other HEMOGLOBIN SAN DIEGO 2017-12-12 no assertion criteria provided literature only
OMIM RCV000641606 SCV000763248 pathogenic Erythrocytosis 6, familial 1995-01-01 no assertion criteria provided literature only

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