Submissions for variant NM_000538.4(RFXAP):c.127C>T (p.Gln43Ter)

gnomAD frequency: 0.00002  dbSNP: rs1313207845

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686231	SCV000813740	pathogenic	MHC class II deficiency	2024-04-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln43*) in the RFXAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RFXAP are known to be pathogenic (PMID: 9118943, 22390233). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RFXAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 566425). For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002282326	SCV002009088	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000686231	SCV002570640	likely pathogenic	MHC class II deficiency	2022-07-14	criteria provided, single submitter	clinical testing	Variant summary: RFXAP c.127C>T (p.Gln43X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.4e-05 in 147392 control chromosomes. To our knowledge, no occurrence of c.127C>T in individuals affected with Bare Lymphocyte Syndrome 2 - RFXAP Related and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002282326	SCV002571548	pathogenic	not provided	2022-09-04	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614)
3billion	RCV000686231	SCV003841703	pathogenic	MHC class II deficiency	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000566425 / PMID: 31589614). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV005010678	SCV005634008	likely pathogenic	MHC class II deficiency 4	2024-06-11	criteria provided, single submitter	clinical testing