Submissions for variant NM_005094.4(SLC27A4):c.899A>G (p.Gln300Arg)

gnomAD frequency: 0.00006  dbSNP: rs137853134

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000006102	SCV001443767	pathogenic	Ichthyosis prematurity syndrome	2020-03-25	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in multiple individuals with Ichthyosis Prematurity Syndrome (IPS; PMIDs: 19631310, 27224495, 21450060). The p.Gln300Arg variant is a frequent ancestral pathogenic variant in the Scandinavian population (PMID: 27224495). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0005% (14/282772) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.899A>G (p.Gln300Arg) variant on protein function. Based on the available evidence, the c.899A>G (p.Gln300Arg) variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000006102	SCV002020693	pathogenic	Ichthyosis prematurity syndrome	2021-10-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512818	SCV003441464	pathogenic	not provided	2024-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 300 of the SLC27A4 protein (p.Gln300Arg). This variant is present in population databases (rs137853134, gnomAD 0.01%). This missense change has been observed in individual(s) with ichthyosis prematurity syndrome (PMID: 19631310, 27224495). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC27A4 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398450	SCV004122179	likely pathogenic	Lamellar ichthyosis	2023-10-03	criteria provided, single submitter	clinical testing	Variant summary: SLC27A4 c.899A>G (p.Gln300Arg) results in a conservative amino acid change located in the AMP-dependent synthetase/ligase domain (IPR000873) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC27A4 causing Lamellar Ichthyosis (4.4e-05 vs 0.0005), allowing no conclusion about variant significance. c.899A>G has been reported in the literature in individuals affected with Lamellar Ichthyosis (examples: Lwin_2016 and Klar_2009). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that this variant protein can inhibit 11-cis-retinol synthesis (Li_2020). The following publications have been ascertained in the context of this evaluation (PMID: 19631310, 31595490, 27224495). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002512818	SCV005888860	pathogenic	not provided	2024-09-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect of this variant (PMID: 31595490); 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: 31168818, Darwish2024[Abstract], 31595490, 19631310, 27224495)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000006102	SCV005914975	pathogenic	Ichthyosis prematurity syndrome	2023-09-18	criteria provided, single submitter	research
OMIM	RCV000006102	SCV000026284	pathogenic	Ichthyosis prematurity syndrome	2009-08-01	no assertion criteria provided	literature only