Submissions for variant NM_014140.4(SMARCAL1):c.2450G>A (p.Arg817His)

gnomAD frequency: 0.00001  dbSNP: rs1172616375

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001336147	SCV001529456	uncertain significance	Schimke immuno-osseous dysplasia	2018-09-26	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001336147	SCV003255804	uncertain significance	Schimke immuno-osseous dysplasia	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 817 of the SMARCAL1 protein (p.Arg817His). 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 missense change has been observed in individual(s) with schimke immune-osseous dysplasia and/or SMARCAL1-related conditions (PMID: 28204945, 29282041). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1033661). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV004719137	SCV005325906	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28204945, 31275356, 29282041)
PreventionGenetics, part of Exact Sciences	RCV004751960	SCV005360760	uncertain significance	SMARCAL1-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The SMARCAL1 c.2450G>A variant is predicted to result in the amino acid substitution p.Arg817His. This variant has been reported in the compound heterozygous state with a second SMARCAL1 variant in an individual with Schimke immuno-osseous dysplasia (SIOD) (Liu et al. 2017. PubMed ID: 29282041). It has also been reported in the compound heterozygous state in an individual from a cohort of patients with steroid-resistant nephrotic syndrome (SRNS) (Wang et al. 2017. PubMed ID: 28204945). This variant is reported in 0.0039% of alleles in individuals of South Asian descent in gnomAD. Of note, a different missense substitution at the same amino acid residue (p.Arg817Cys) has also been reported in the compound heterozygous state in individuals with SIOD or SMARCAL1-related phenotypes (Morimoto et al. 2012. PubMed ID: 22998683; Table S3, Nagano et al. 2022. PubMed ID: 36176665). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.