Submissions for variant NM_005262.3(GFER):c.580C>T (p.Arg194Cys)

gnomAD frequency: 0.00003  dbSNP: rs780851934

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272990	SCV002557509	likely pathogenic	Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 3). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (8 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. The alternate p.(Arg194His) variant has been shown to result in destabilisation and mislocalisation of GFER protein, demonstrating the importance of this residue (PMID: 19409522). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. (p.(Arg194His); Clinvar, PMID: 19409522) (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. Homozygous in a patient with cardiorespiratory insufficiency and metabolic acidosis (PMID: 28939701). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101546	SCV003461736	uncertain significance	not provided	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 194 of the GFER protein (p.Arg194Cys). This variant is present in population databases (rs780851934, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of GFER-related conditions (PMID: 28939701). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Arg194 amino acid residue in GFER. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19409522, 26018198, 26944241). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.