ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.190C>T (p.His64Tyr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.190C>T (p.His64Tyr)
Variation ID: 15256 Accession: VCV000015256.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226702 (GRCh38) [ NCBI UCSC ] 11: 5247932 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 13, 2018 Jan 7, 2023 Jul 2, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.190C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.His64Tyr missense NC_000011.10:g.5226702G>A NC_000011.9:g.5247932G>A NG_000007.3:g.70914C>T NG_042296.1:g.233G>A NG_046672.1:g.4637G>A NG_059281.1:g.5370C>T LRG_1232:g.5370C>T LRG_1232t1:c.190C>T LRG_1232p1:p.His64Tyr P68871:p.His64Tyr - Protein change
- H64Y
- Other names
- H63Y
- Hb M-Saskatoon
- Hb Hörlein-Weber
- Hb Leipzig
- Hb M-Arhus
- Hb M-Chicago
- Hb M-Emory
- Hb M-Erlangen
- Hb M-Hamburg
- Hb M-Hida
- Hb M-Kurume
- Hb M-Radom
- Hb Novi Sad
- Canonical SPDI
- NC_000011.10:5226701:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HBB | - | - |
GRCh38 GRCh37 |
22 | 1831 | |
LOC106099062 | - | - | - | GRCh38 | - | 859 |
LOC107133510 | - | - | - | GRCh38 | - | 1781 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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HEMOGLOBIN M (SASKATOON)
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other (1) |
no assertion criteria provided
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May 10, 2018 | RCV000016466.8 |
HEMOGLOBIN M (RADOM) METHEMOGLOBINEMIA, BETA TYPE
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Pathogenic (1) |
no assertion criteria provided
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Jun 1, 1995 | RCV000641524.1 |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 2, 2019 | RCV000988480.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 16, 2019 | RCV001266995.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138217.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jul 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360657.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HBB c.190C>T (p.His64Tyr) results in a conservative amino acid change located in a heme binding site (InterPro) of the encoded protein sequence. Four … (more)
Variant summary: HBB c.190C>T (p.His64Tyr) results in a conservative amino acid change located in a heme binding site (InterPro) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251426 control chromosomes (gnomAD). The variant (also known as Hb M-Saskatoon) is widely regarded as causing hemoglobin M (HbM) disease, and has been reported in the literature in several affected individuals (e.g. Efremov_1974, Waye_1994, Suryantoro_1995, Kedar_2005, Brunner-Agten_2010, Garcia-Morin_2019). The disorder was observed to be inherited in an autosomal dominant pattern, often occurring as a de novo mutation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 16, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445176.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Methemoglobinemia (present)
Sex: male
Ethnicity/Population group: Caucasian
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other
(May 10, 2018)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN M (SASKATOON)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036734.5
First in ClinVar: Apr 04, 2013 Last updated: May 13, 2018 |
Comment on evidence:
This was the abnormal hemoglobin in the family with autosomal dominant cyanosis (617971) reported by Baltzan and Sugarman (1950). See Horlein and Weber (1948), Heck … (more)
This was the abnormal hemoglobin in the family with autosomal dominant cyanosis (617971) reported by Baltzan and Sugarman (1950). See Horlein and Weber (1948), Heck and Wolf (1958), Gerald and George (1959), Gerald and Efron (1961), Shibata et al. (1961, 1965), Heller (1962), Josephson et al. (1962), Hanada et al. (1964), Murawski et al. (1965), Hobolth (1965), Betke et al. (1966), Efremov et al. (1974), Kohne et al. (1975), and Baine et al. (1980). Suryantoro et al. (1995) described the his63-to-tyr mutation in an Indonesian boy with methemoglobinemia and mild hemolysis. The mutation was inherited from the mother. The report further demonstrated the worldwide distribution of Hb M-Saskatoon. (less)
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Pathogenic
(Jun 01, 1995)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN M (RADOM) METHEMOGLOBINEMIA, BETA TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000763166.1
First in ClinVar: May 28, 2018 Last updated: May 28, 2018 |
Comment on evidence:
This was the abnormal hemoglobin in the family with autosomal dominant cyanosis (617971) reported by Baltzan and Sugarman (1950). See Horlein and Weber (1948), Heck … (more)
This was the abnormal hemoglobin in the family with autosomal dominant cyanosis (617971) reported by Baltzan and Sugarman (1950). See Horlein and Weber (1948), Heck and Wolf (1958), Gerald and George (1959), Gerald and Efron (1961), Shibata et al. (1961, 1965), Heller (1962), Josephson et al. (1962), Hanada et al. (1964), Murawski et al. (1965), Hobolth (1965), Betke et al. (1966), Efremov et al. (1974), Kohne et al. (1975), and Baine et al. (1980). Suryantoro et al. (1995) described the his63-to-tyr mutation in an Indonesian boy with methemoglobinemia and mild hemolysis. The mutation was inherited from the mother. The report further demonstrated the worldwide distribution of Hb M-Saskatoon. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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First observation of hemoglobin m saskatoon (ß63 (e7) his>tyr(c-t)) in the iraqi population. | Akar N | Turkish journal of haematology : official journal of Turkish Society of Haematology | 2012 | PMID: 24744675 |
First observation of hemoglobin Crete [Beta129(H7) Ala>Pro] in the Turkish population. | Arslan Ç | Turkish journal of haematology : official journal of Turkish Society of Haematology | 2011 | PMID: 27264598 |
Compound heterozygosity of Hb Hamilton and de novo mutated HbM Saskatoon. | Brunner-Agten S | Annals of hematology | 2010 | PMID: 19727720 |
Congenital methemoglobinemia caused by Hb-MRatnagiri (beta-63CAT-->TAT, His-->Tyr) in an Indian family. | Kedar PS | American journal of hematology | 2005 | PMID: 15929117 |
Crystal structure of deoxy-human hemoglobin beta6 Glu --> Trp. Implications for the structure and formation of the sickle cell fiber. | Harrington DJ | The Journal of biological chemistry | 1998 | PMID: 9830011 |
Studies of the oxidation states of hemoglobin M Boston and hemoglobin M Saskatoon in blood by EPR spectroscopy. | Nagai M | Biochemical and biophysical research communications | 1995 | PMID: 7755625 |
C to T transition at the first nucleotide of codon 63 of the beta-globin gene corresponding to hemoglobin M-Saskatoon in an Indonesian boy. | Suryantoro P | The Japanese journal of human genetics | 1995 | PMID: 7663000 |
Determination of the amounts and oxidation states of hemoglobins M Boston and M Saskatoon in single erythrocytes by infrared microspectroscopy. | Dong A | The Journal of biological chemistry | 1994 | PMID: 7929232 |
De novo beta-globin gene mutation [beta 63(E7)His-->Tyr] giving rise to Hb M disease in a Newfoundlander. | Waye JS | Hemoglobin | 1994 | PMID: 7713749 |
Hemoglobin M Saskatoon (alpha 2 beta 2 63(E7) His----Tyr) in an Algerian family. | Arbane-Dahmane M | Hemoglobin | 1985 | PMID: 4086306 |
Enzymatic reduction of hemoglobins M Milwaukee-1 and M Saskatoon by NADH-cytochrome b5 reductase and NADPH-flavin reductase purified from human erythrocytes. | Nagai M | The Journal of biological chemistry | 1980 | PMID: 7372598 |
Biosynthetic evidence for instability of HB M Saskatoon. | Baine RM | Hemoglobin | 1980 | PMID: 6248489 |
[HbM Erlangen: alpha2beta263(e7) tyr. New mutation with haemolysis and NADH-methaemoglobin reductase deficiency (author's transl)]. | Kohne E | Zeitschrift fur Kinderheilkunde | 1975 | PMID: 1163074 |
A second family with hemoglobin M Saskatoon in Saskatchewan. | Vella F | Clinical biochemistry | 1974 | PMID: 4841979 |
Haemoglobin M Saskatoon and haemoglobin M Hyde Park in two Yugoslavian families. | Efremov GD | Scandinavian journal of haematology | 1974 | PMID: 4413625 |
[HbM Hamburg, a beta chain anomaly: alpha-2-beta-2-63Tyr (equals HbM Saskatoon)]. | Betke K | Klinische Wochenschrift | 1966 | PMID: 5996551 |
HEMOGLOBIN MARHUS. I. CLINICAL FAMILY STUDY. | HOBOLTH N | Acta paediatrica Scandinavica | 1965 | PMID: 14343445 |
Hemoglobin M disease in Japan. | Shibata S | Israel journal of medical sciences | 1965 | PMID: 5856115 |
Observations on the structure and behavior of hemoglobin MRadom. | Murawski K | Archives of biochemistry and biophysics | 1965 | PMID: 5851873 |
A new variant of hemoglobin M disease: hemoglobin M-Chicago. | JOSEPHSON AM | The Journal of laboratory and clinical medicine | 1962 | PMID: 14452533 |
Spectroscopic characterization of Hb M-Iwate and Hb M-Kurume, the two variants of hemoglobin M found in Japan. | SHIBATA S | Nihon Ketsueki Gakkai zasshi : journal of Japan Haematological Society | 1961 | PMID: 13911805 |
Chemical studies of several varieties of Hb M. | GERALD PS | Proceedings of the National Academy of Sciences of the United States of America | 1961 | PMID: 13897827 |
Second spectroscopically abnormal methemoglobin associated with hereditary cyanosis. | GERALD PS | Science (New York, N.Y.) | 1959 | PMID: 13634986 |
[Congenital cardiac defect with cyanosis caused by pathological blood pigment (hemoglobin M)]. | HECK W | Annales paediatrici. International review of pediatrics | 1958 | PMID: 13509426 |
HEREDITARY CYANOSIS. | Baltzan DM | Canadian Medical Association journal | 1950 | PMID: 20324533 |
[About chronic familial methemoglobinemia and a new modification of methemoglobin]. | HORLEIN H | Deutsche medizinische Wochenschrift (1946) | 1948 | PMID: 18105244 |
Hanada, M., Ohta, Y., Imamura, T., Fejimura, T., Kawasaki, K., Kosaka, K., Yamaoka, K., Seita, M. Studies of abnormal hemoglobins in western Japan. (Abstract) Jpn. J. Hum. Genet. 9: 253-254, 1964. | - | - | - | - |
Heller, P., Coleman, R. D., Yakulis, V. Hemoglobin M (Hyde Park): a new variant of abnormal methemoglobin in a Negro. (Abstract) J. Clin. Invest. 45: 1021, 1966. | - | - | - | - |
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Text-mined citations for rs33922873 ...
HelpRecord last updated Jan 07, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.