Submissions for variant NM_173630.4(RTTN):c.2315G>A (p.Arg772His)

dbSNP: rs751344541

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003085975	SCV003473207	uncertain significance	not provided	2024-10-24	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 772 of the RTTN protein (p.Arg772His). 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 RTTN-related conditions (PMID: 29883675). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2159547). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RTTN protein function with a positive predictive value of 80%. 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.
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV003326021	SCV003853430	likely pathogenic	Microcephalic primordial dwarfism due to RTTN deficiency	2023-03-23	criteria provided, single submitter	clinical testing
Laboratoire de Cytogenomique, Chu Angers	RCV003326021	SCV005423734	uncertain significance	Microcephalic primordial dwarfism due to RTTN deficiency	2024-11-20	criteria provided, single submitter	clinical testing	NM_173630.4(RTTN):c.2315G>A : Very rare variant in population databases, with high coverage ; Detected in trans with a pathogenic variant ; Patient’s phenotype is specific for this disease with a single genetic etiology (microcephaly and lissencephaly) ; Variant in trans : NM_173630.4(RTTN):c.3449T>A (Pathogenic) : Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease ; Very rare variant in population databases, with high coverage ; Detected in trans with a uncertain significant variant ; Patient’s phenotype is specific for this disease with a single genetic etiology (microcephaly and lissencephaly) ; Described in ClinVar as [Pathogenic]. Clinvar id is 1325024.