Submissions for variant NM_000061.3(BTK):c.720A>C (p.Glu240Asp)

gnomAD frequency: 0.00006  dbSNP: rs141590686

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534777	SCV000634733	uncertain significance	X-linked agammaglobulinemia with growth hormone deficiency	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 240 of the BTK protein (p.Glu240Asp). This variant is present in population databases (rs141590686, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with BTK-related conditions. ClinVar contains an entry for this variant (Variation ID: 461818). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BTK protein function. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272281	SCV002557866	uncertain significance	X-linked agammaglobulinemia	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to an aspartic acid (exon 8). (N) 0253 - Variant is hemizygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes, 2 hemizygotes). (P) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (SH3 domain; PMID: 24001798, NCBI, Decipher, PDB). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are inconclusive. This variant has been previously reported as VUS (ClinVar). In addition, it has been reported in a patient with X-linked agammaglobulinemia, however, there was no conclusion regarding pathogenicity. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
PreventionGenetics, part of Exact Sciences	RCV003419941	SCV004109464	uncertain significance	BTK-related disorder	2022-10-12	criteria provided, single submitter	clinical testing	The BTK c.720A>C variant is predicted to result in the amino acid substitution p.Glu240Asp. This variant has been reported in an individual with X-linked agammaglobulinemia, however there was no conclusion regarding pathogenicity of this variant (Abbott et al. 2013. PubMed ID: 24001798). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD, including two hemizygous individuals (http://gnomad.broadinstitute.org/variant/X-100615612-T-G). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.