Submissions for variant NM_000517.4(HBA2):c.427T>C (p.Ter143Gln)

gnomAD frequency: 0.00006  dbSNP: rs41464951

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508088	SCV000603872	pathogenic	not provided	2023-11-30	criteria provided, single submitter	clinical testing	The Hb Constant Spring variant (HbCS, HBA2: c.427T>C; p.Ter143Gln, also known as Ter142Gln when numbered from the mature protein, rs41464951, HbVar ID: 703) is usually asymptomatic in the heterozygous state, but may be associated with microcytosis and mild hypochromia. Homozygosity for HbCS is characterized by overt hemolytic anemia, jaundice and splenomegaly, while HbCS paired with an alpha zero-thalassemia deletion commonly results in HbH disease (Lie-Injo 1974, Nguyen 2014, HbVar database). This variant is reported in ClinVar (Variation ID: 15624), and is found in the general population with an overall allele frequency of 0.006% (16/274,340 alleles) in the Genome Aggregation Database. This variant abolishes the canonical termination codon, resulting in an unstable, elongated protein (HbVar database). Based on available information, the HbCS variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Lie-Injo L et al. Homozygous state for Hb Constant Spring (slow-moving Hb X components). Blood. 1974 Feb;43(2):251-9. PMID: 4810076. Nguyen V et al. Hemoglobin Constant Spring is markedly high in women of an ethnic minority group in Vietnam: a community-based survey and hematologic features. Blood Cells Mol Dis. 2014 Apr;52(4):161-5. PMID: 24368026.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000169546	SCV000746425	pathogenic	alpha Thalassemia	2017-12-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508088	SCV000888134	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	The HBA2 c.427T>C (p.*143Glnext*31) variant disrupts the translation stop codon of the HBA2 mRNA and is predicted to cause abnormal HBA2 protein elongation. In the published literature and online databases, this variant has been reported to be damaging to HBA2 function and results in an unstable protein (PMID: 7969150 (1994)). Additionally, this variant has been reported in individuals with Hb H disease that are compound heterozygous with other pathogenic HBA2 variants, such as Hb Adana (PMIDs: 24829075 (2014), 27271331 (2016)), Hb Pakse (PMIDs: 7502632 (1995), 28244614 (2018), 30615015 (2019)), and Hb Quong (PMID: 26956449 (2016)). This variant is commonly seen with the SEA alpha-1 deletion (PMIDs: 11836160 (2002), 32925409 (2021), 36459106 (2023)). Based on the available information, this variant is classified as pathogenic.
Invitae	RCV000508088	SCV000954178	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change disrupts the translational stop signal of the HBA2 mRNA. It is expected to extend the length of the HBA2 protein by 31 additional amino acid residues. This variant is present in population databases (rs41464951, gnomAD 0.07%). This protein extension has been observed in individual(s) with HBA2-related conditions (PMID: 2298455, 4944483, 12393486, 20507641). It is commonly reported in individuals of Southeast Asian ancestry (PMID: 2298455, 4944483, 12393486, 20507641). This variant is also known as Constant Spring. ClinVar contains an entry for this variant (Variation ID: 15624). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects HBA2 function (PMID: 6725554, 9057661). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000169546	SCV001194098	pathogenic	alpha Thalassemia	2019-12-20	criteria provided, single submitter	clinical testing	NM_000517.4(HBA2):c.427T>C(*143Qext*31, aka Hb Constant Spring) is classified as pathogenic in the context of alpha thalassemia and is classified as an alpha-plus variant. Sources cited for classification include the following: PMID 4944483, 12393486, 7327587, 2298455 and 17164653. Classification of NM_000517.4(HBA2):c.427T>C(*143Qext*31, aka Hb Constant Spring) is based on the following criteria: This variant is predicted to result in protein elongation in a gene and is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000508088	SCV001763953	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	The variant eliminates the normal Stop codon and replaces it with a Glutamine codon, ultimately extending the protein by 31 amino acids at the C-terminal end of the protein; This variant is associated with the following publications: (PMID: 26757782, 24368026, 21077767, 24829075, 25523870, 23637094, 20931520, 3177365, 25897478, 26956449, 30626226, 30615015, 30275481, 34272389, 32925409, 32860378, 32338097, 29627922)
Genetics and Molecular Pathology, SA Pathology	RCV000169546	SCV002556998	pathogenic	alpha Thalassemia	2022-07-27	criteria provided, single submitter	clinical testing	PS4, PM1, PM4, PP1, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000169546	SCV003921986	pathogenic	alpha Thalassemia	2020-11-05	criteria provided, single submitter	clinical testing	0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0208 - Variant is predicted to result in an elongated protein (exon 3 of 3). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity (ClinVar). Four other elongated protein have been reported as pathogenic. (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals. This is the most common pathogenic mutation reported in alpha thalassemia, known as the Hb Constant Sprint variant (ClinVar, PMID: 26757782). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
OMIM	RCV000016891	SCV000037161	other	Hemoglobin constant spring	2022-09-12	no assertion criteria provided	literature only
OMIM	RCV000022602	SCV000043891	pathogenic	Hemoglobin H disease, nondeletional	1992-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000169546	SCV000503052	not provided	alpha Thalassemia		no assertion provided	literature only
GenomeConnect, ClinGen	RCV000169546	SCV001423188	not provided	alpha Thalassemia		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 07-24-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000169546	SCV002093851	pathogenic	alpha Thalassemia	2021-09-02	no assertion criteria provided	clinical testing