NM_002351.5(SH2D1A):c.23A>C (p.His8Pro) AND X-linked lymphoproliferative disease due to SH2D1A deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 28, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV003228222.2

Allele description

NM_002351.5(SH2D1A):c.23A>C (p.His8Pro)

Gene:

SH2D1A:SH2 domain containing 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq25

Genomic location:

Preferred name:

NM_002351.5(SH2D1A):c.23A>C (p.His8Pro)

HGVS:

NC_000023.11:g.124346665A>C
NG_007464.1:g.5366A>C
NG_033796.2:g.391106A>C
NM_001114937.3:c.23A>C
NM_002351.5:c.23A>CMANE SELECT
NP_001108409.1:p.His8Pro
NP_002342.1:p.His8Pro
NP_002342.1:p.His8Pro
LRG_106t1:c.23A>C
LRG_106:g.5366A>C
LRG_106p1:p.His8Pro
LRG_782:g.391106A>C
NC_000023.10:g.123480515A>C
NM_002351.4:c.23A>C

Protein change:

H8P

Molecular consequence:

NM_001114937.3:c.23A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002351.5:c.23A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked lymphoproliferative disease due to SH2D1A deficiency (XLP1)
Synonyms:: IMMUNODEFICIENCY 5; IMMUNODEFICIENCY, X-LINKED PROGRESSIVE COMBINED VARIABLE; INFECTIOUS MONONUCLEOSIS, SEVERE, SUSCEPTIBILITY TO; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0024551; MedGen: C5399825; Orphanet: 2442; OMIM: 308240

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003924358	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004298980	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16328363, 15682426, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003924358

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 8, 2023)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004298980

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 28, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

X-linked lymphoproliferative disease associated with hypogammaglobulinemia and growth-hormone deficiency.

Alangari A, Abobaker A, Kanegane H, Miyawaki T.

Eur J Pediatr. 2006 Mar;165(3):165-7. Epub 2005 Nov 17.

PubMed [citation]

PMID:: 16328363

See all PubMed Citations (4)

Details of each submission

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV003924358.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	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		not provided	not provided	not provided	not provided

From Invitae, SCV004298980.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 8 of the SH2D1A protein (p.His8Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked lymphoproliferative disease (PMID: 16328363). ClinVar contains an entry for this variant (Variation ID: 2501803). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.His8 amino acid residue in SH2D1A. Other variant(s) that disrupt this residue have been observed in individuals with SH2D1A-related conditions (PMID: 15682426), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Apr 6, 2024

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