ClinVar Miner

Submissions for variant NM_001301365.1(LYST):c.3310C>T (p.Arg1104Ter) (rs80338652)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000055730 SCV000355768 likely pathogenic Chédiak-Higashi syndrome 2017-04-27 criteria provided, single submitter clinical testing The LYST c.3310C>T (p.Arg1104Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg1104Ter has been reported in two studies in which it is found in a homozygous state in two individuals with Chediak-Higashi syndrome (Nagle et al. 1996; Certain et al. 2000). Control data are unavailable for this variant which is reported at a frequency of 0.000024 in the total population of the Exome Aggregation Consortium. The evidence for this variant is limited. However, based on the evidence and the potential impact of stop-gained variants, the p.Arg1104Ter variant is classified as likely pathogenic for Chediak-Higashi syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000482098 SCV000565883 pathogenic not provided 2017-03-23 criteria provided, single submitter clinical testing The R1104X pathogenic variant in the LYST gene has been reported previously in the homozygous and compound heterozygous state in association with Chediak-Higashi syndrome (CHS) (Jin et al., 2017; Certain et al., 2000; Nagle et al., 1996). Two siblings compound heterozygous for the R1104X variant were noted to have an atypical presentation of CHS with partial oculocutaneous albinism, silvery hair, abnormal peripheral blood smears, frequent upper respiratory infections, and marginal intelligence, without bleeding tendency and severe immunodeficiency (Jin et al., 2017). An individual homozygous for the R1104X variant was diagnosed with CHS at 2.5 years of age and had a more severe immunodeficiency phenotype with the occurrence of the accelerated phase requiring a bone marrow transplant, while the other reported homozygous individual had a late-onset presentation in his twenties with albinism, recurrent skin infections, neuropathy and mild intellectual disability (Certain et al., 2000; Nagle et al., 1996). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1104X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R1104X as a pathogenic variant.
Invitae RCV000055730 SCV000817679 pathogenic Chédiak-Higashi syndrome 2018-05-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1104*) in the LYST gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80338652, ExAC 0.006%). This variant has been observed in individuals with Chediak-Higashi syndrome and has been observed to segregate with disease in a family (PMID: 8896560, 28193763, 28145517, 10648412). ClinVar contains an entry for this variant (Variation ID: 3809). Experimental studies have shown that patient-derived cells that carry both the p.Arg1104* variant and a missense variant (p.Gly3408Arg) demonstrate altered cytotoxic granule number and morphology compared to control NK cells (PMID: 28458669). However, the effect of the p.Arg1104* variant alone was not assessed. Loss-of-function variants in LYST are known to be pathogenic (PMID: 9215679, 11857544). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004013 SCV000024179 pathogenic Chediak-Higashi syndrome, adult type 1996-11-01 no assertion criteria provided literature only
GeneReviews RCV000055730 SCV000086668 pathologic Chédiak-Higashi syndrome 2012-02-16 no assertion criteria provided curation Converted during submission to Pathogenic.

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