Variant: NM_000022.4(ADA):c.937C>T (p.Arg313Trp)

CA9871463

1195941 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 91eca944-2e6a-4f9c-ac73-6f66e12b9a9d

Approved on: 2024-04-23

Published on: 2024-04-23

HGVS expressions

NM_000022.4:c.937C>T
NM_000022.4(ADA):c.937C>T (p.Arg313Trp)
NC_000020.11:g.44621056G>A
CM000682.2:g.44621056G>A
NC_000020.10:g.43249697G>A
CM000682.1:g.43249697G>A
NC_000020.9:g.42683111G>A
NG_007385.1:g.35680C>T
ENST00000492931.6:n.1104C>T
ENST00000536076.2:c.784C>T
ENST00000536532.6:c.*80C>T
ENST00000537820.2:c.865C>T
ENST00000539235.6:c.*321C>T
ENST00000695889.1:c.412C>T
ENST00000695890.1:n.4432C>T
ENST00000695891.1:c.477C>T
ENST00000695927.1:c.1015C>T
ENST00000695949.1:c.862C>T
ENST00000695956.1:c.92C>T
ENST00000695957.1:c.*428C>T
ENST00000695991.1:c.475C>T
ENST00000695992.1:c.*80C>T
ENST00000695993.1:c.937C>T
ENST00000695994.1:c.*80C>T
ENST00000695995.1:c.547C>T
ENST00000695996.1:n.1019C>T
ENST00000696003.1:n.2721C>T
ENST00000696004.1:n.1105C>T
ENST00000696005.1:c.387C>T
ENST00000696006.1:c.*80C>T
ENST00000696007.1:c.864C>T
ENST00000696008.1:n.3291C>T
ENST00000696017.1:c.934C>T
ENST00000696034.1:c.*80C>T
ENST00000696035.1:n.1123C>T
ENST00000696036.1:n.1638C>T
ENST00000696037.1:n.2614C>T
ENST00000696038.1:c.*694C>T
ENST00000696039.1:n.1301C>T
ENST00000696058.1:c.934C>T
ENST00000696059.1:c.*882C>T
ENST00000696060.1:c.1006C>T
ENST00000696061.1:c.934C>T
ENST00000696062.1:c.1000C>T
ENST00000696063.1:c.1012C>T
ENST00000696064.1:c.784C>T
ENST00000696065.1:c.259C>T
ENST00000696072.1:n.292C>T
ENST00000696073.1:n.1248C>T
ENST00000696074.1:n.488C>T
ENST00000696075.1:c.*907C>T
ENST00000696076.1:c.1006C>T
ENST00000696077.1:c.931C>T
ENST00000696078.1:c.934C>T
ENST00000696079.1:c.934C>T
ENST00000696080.1:c.937C>T
ENST00000696081.1:n.1056C>T
ENST00000696082.1:c.1012C>T
ENST00000696083.1:n.1894C>T
ENST00000696084.1:n.1114C>T
ENST00000696104.1:c.*6C>T
ENST00000372874.9:c.937C>T
ENST00000372874.8:c.937C>T
ENST00000372887.5:c.152-2877G>A
ENST00000464097.5:n.687C>T
ENST00000492931.5:n.1097C>T
ENST00000536532.5:c.*80C>T
ENST00000537820.1:c.865C>T
ENST00000539235.5:c.*321C>T
NM_000022.2:c.937C>T
NM_000022.3:c.937C>T
NM_001322050.1:c.532C>T
NM_001322051.1:c.865C>T
NR_136160.1:n.1023C>T
NM_001322050.2:c.532C>T
NM_001322051.2:c.865C>T
NR_136160.2:n.964C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BS2 PM5

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.937C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 313 (p.Arg313Trp). The filtering allele frequency (the upper threshold of the 95% CI of 25/1180022 alleles) of the c.937C>T variant in ADA is 0.00001454 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Another missense variant [c.938G>A, p.Arg313Gln] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met). To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting.

Met criteria codes

• PM2_Supporting: The filtering allele frequency (the upper threshold of the 95% CI of 25/1180022 alleles) of the c.937C>T variant in ADA is 0.00001454 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: Another missense variant [c.938G>A, p.Arg313Gln] in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not met).