Submissions for variant NM_001101426.4(CRPPA):c.643C>T (p.Gln215Ter)

gnomAD frequency: 0.00003  dbSNP: rs370627877

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000342780	SCV000334524	pathogenic	not provided	2015-08-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000342780	SCV001168428	pathogenic	not provided	2019-03-27	criteria provided, single submitter	clinical testing	The Q215X variant in the ISPD gene has been reported previously in a patient with Walker-Warburg syndrome, who also harbored an exon level deletion of the ISPD gene (Willer et at., 2012). Q215X has also been identified in the compound heterozygous state with a missense variant in a patient with congenital muscular dystrophy without CNS involvement (Cirak et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional characterization of the Q215X variant indicates loss of both functional glycosylation and receptor function (Willer et al., 2012). The Q215X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q215X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229838	SCV002508469	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7; Autosomal recessive limb-girdle muscular dystrophy type 2U	2022-09-17	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 282846). This premature translational stop signal has been observed in individual(s) with ISPD-related conditions (PMID: 22522420, 23288328). This variant is present in population databases (rs370627877, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Gln215*) in the ISPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000342780	SCV004235443	pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000844945	SCV000986764	not provided	ISPD-related disorder		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 05/09/2018 by Lab or GTR ID . GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.