Submissions for variant NM_000996.4(RPL35A):c.125A>G (p.Tyr42Cys)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002308738	SCV002600916	likely pathogenic	not provided	2022-05-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25424902, 32241839, 29146883)
Ambry Genetics	RCV002427776	SCV002680495	likely pathogenic	Diamond-Blackfan anemia	2015-04-23	criteria provided, single submitter	clinical testing	The p.Y42C variant (also known as c.125A>G), located in coding exon 2 of the RPL35a gene, results from an A to G substitution at nucleotide position 125. The tyrosine at codon 42 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in two unrelated individuals with Diamond Blackfan anemia; the variant was not carried by their unaffected parents and considered to be likely de novo in the two probands (Wang R et al. Br J Haematol. 2015;168(6):854-64). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003514552	SCV004292263	uncertain significance	Diamond-Blackfan anemia 5	2023-02-11	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 42 of the RPL35A protein (p.Tyr42Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RPL35A-related condition (PMID: 25424902, 29146883). ClinVar contains an entry for this variant (Variation ID: 1723464). 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. 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.
CeGaT Center for Human Genetics Tuebingen	RCV002308738	SCV004704303	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RPL35A: PM2, PM6, PS4:Moderate, PP3