NM_000517.6(HBA2):c.314G>A (p.Cys105Tyr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001811170.18

Allele description [Variation Report for NM_000517.6(HBA2):c.314G>A (p.Cys105Tyr)]

NM_000517.6(HBA2):c.314G>A (p.Cys105Tyr)

Genes:

LOC106804612:hemoglobin subunit alpha 2 recombination region [Gene]
HBA2:hemoglobin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000517.6(HBA2):c.314G>A (p.Cys105Tyr)

Other names:

C104Y

HGVS:

NC_000016.10:g.173485G>A
NG_000006.1:g.34348G>A
NG_046165.1:g.3224G>A
NG_059186.1:g.1835G>A
NG_059271.1:g.5639G>A
NM_000517.6:c.314G>AMANE SELECT
NP_000508.1:p.Cys105Tyr
LRG_1240t1:c.314G>A
LRG_1225:g.1835G>A
LRG_1240:g.5639G>A
LRG_1240p1:p.Cys105Tyr
NC_000016.9:g.223484G>A

Protein change:

C105Y; CYS104TYR

Links:

OMIM: 141850.0031; dbSNP: rs41417548

NCBI 1000 Genomes Browser:

rs41417548

Molecular consequence:

NM_000517.6:c.314G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002048354	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Apr 9, 2021)	germline	clinical testing	Citation Link,
SCV004131653	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002048354

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Likely pathogenic
(Apr 9, 2021)

germline

clinical testing

Citation Link,

SCV004131653

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Aug 1, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The Hb Sallanches variant (HBA2: c.314G>A; p.Cys105Tyr, also known as Cys104Tyr when numbered from the mature protein, rs41417548) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals with Hb H disease (Hb Var and references therein, Sharma 2020). Functional analyses show the variant protein is unstable and display a defect in binding with alpha-hemoglobin stabilizing protein (Sharma 2020, Wajcman 2011). This variant is reported in ClinVar (Variation ID: 15656). This variant is found in the South Asian population with an allele frequency of 0.017% (5/30278 alleles) in the Genome Aggregation Database. The cysteine at codon 105 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.678). Based on available information, this variant is considered to be likely pathogenic. References: Hb Var for Hb Sallanches: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=167&.cgifields=histD Sharma P et al. HbH disease due to compound heterozygosity for hemoglobins Zürich-Albisrieden and Sallanches. Pediatr Blood Cancer. 2020 Apr;67(4):e28161. PMID: 31930682. Wajcman H et al. a-Hemoglobin stabilizing protein: a modulating factor in thalassemias? Hemoglobin. 2011;35(5-6):463-8. PMID: 21950764.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004131653.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

HBA2: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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