Submissions for variant NM_001126121.2(SLC25A19):c.622C>T (p.Pro208Ser)

gnomAD frequency: 0.00023  dbSNP: rs200276538

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000713308	SCV000114020	uncertain significance	not provided	2013-08-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000398031	SCV000406423	uncertain significance	Amish lethal microcephaly	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000713308	SCV000589688	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SLC25A19 gene. The P208S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P208S variant is observed in 12/65896 (0.02%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P208S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics Inc	RCV000713308	SCV000843900	uncertain significance	not provided	2018-06-15	criteria provided, single submitter	clinical testing
Invitae	RCV000713308	SCV002227544	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 208 of the SLC25A19 protein (p.Pro208Ser). This variant is present in population databases (rs200276538, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC25A19-related conditions. ClinVar contains an entry for this variant (Variation ID: 96021). 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: "Benign"; 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.
Ambry Genetics	RCV002514439	SCV003711144	uncertain significance	Inborn genetic diseases	2022-06-17	criteria provided, single submitter	clinical testing	The c.622C>T (p.P208S) alteration is located in exon 6 (coding exon 4) of the SLC25A19 gene. This alteration results from a C to T substitution at nucleotide position 622, causing the proline (P) at amino acid position 208 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.