Submissions for variant NM_000061.3(BTK):c.1558C>T (p.Arg520Ter)

dbSNP: rs128621201

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000378493	SCV000329169	pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11742281, 15661032, 19039656, 9445504, 27512878, 15661031, 25777788, 7849697, 9545398, 16712653, 31967259, 7880320, 22927353, 21518255, 8834236, 30072168, 29424453, 14974089, 32914284, 33686510, 25525159, 34134972, 34992599, 33225392)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061773	SCV001226529	pathogenic	X-linked agammaglobulinemia with growth hormone deficiency	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg520*) in the BTK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTK are known to be pathogenic (PMID: 15661032, 16862044, 19419768). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked agammaglobulinemia (PMID: 7849721, 7880320, 30072168). This variant is also known as 1690C>T. ClinVar contains an entry for this variant (Variation ID: 11377). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012130	SCV002557123	pathogenic	X-linked agammaglobulinemia	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked agammaglobulinemia 1 (MIM#300755) and isolated growth hormone deficiency type III with agammaglobulinemia (MIM#307200). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in individuals with X-linked agammaglobulinemia (ClinVar, PMID: 30072168). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000012130	SCV005061256	pathogenic	X-linked agammaglobulinemia		criteria provided, single submitter	clinical testing	The observed stop gained c.1558C>T (p.Arg520Ter) variant in BTK gene has been previously reported in multiple individuals affected with Agammaglobulinemia (Tóth et al., 2009; Doğruel et al., 2019; Zhu et al., 1994). The p.Arg520Ter variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). The nucleotide change c.1558C>T in BTK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg520Ter) in the BTK gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in BTK gene have been previously reported to be pathogenic (Tóth et al., 2009). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000012130	SCV000032364	pathogenic	X-linked agammaglobulinemia	1994-10-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000582314	SCV000692193	pathogenic	Autosomal recessive agammaglobulinemia 1	2008-02-14	no assertion criteria provided	clinical testing