Submissions for variant NM_000081.4(LYST):c.1829A>T (p.His610Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541039	SCV000623894	uncertain significance	Chédiak-Higashi syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 610 of the LYST protein (p.His610Leu). This variant is present in population databases (rs145298434, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 454482). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LYST protein function with a negative predictive value of 80%. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000541039	SCV003920178	uncertain significance	Chédiak-Higashi syndrome	2022-11-09	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.09% [10/10620]; https://gnomad.broadinstitute.org/variant/1-235808989-T-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 454482). Evolutionary conservation and computational prediction tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701602	SCV005202798	likely benign	not specified	2024-07-25	criteria provided, single submitter	clinical testing	Variant summary: LYST c.1829A>T (p.His610Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 1607016 control chromosomes, predominantly at a frequency of 0.002 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database (v4.1 dataset) is approximately 1.8-fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome phenotype (0.0011). To our knowledge, no occurrence of c.1829A>T in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 454482). Based on the evidence outlined above, the variant was classified as likely benign.