Submissions for variant NM_017838.4(NHP2):c.289_290del (p.Met97fs)

gnomAD frequency: 0.00002  dbSNP: rs762821341

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239867	SCV001412769	uncertain significance	Dyskeratosis congenita	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met97Valfs*2) in the NHP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the NHP2 protein. This variant is present in population databases (rs762821341, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features compatible with a telomere biology disorder (PMID: 31985013). ClinVar contains an entry for this variant (Variation ID: 965425). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
GeneDx	RCV001760265	SCV002000936	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 57 amino acids are replaced with 1 different amino acid, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in the heterozygous state in two individuals with pulmonary fibrosis and shortened telomeres (Benyelles et al., 2020); Published functional studies in cells from one patient demonstrated an altered pre-rRNA profile suggesting a processing defect, but no reduction in snoRNA levels (Benyelles et al., 2020); This variant is associated with the following publications: (PMID: 31985013)
Sema4, Sema4	RCV001239867	SCV002527219	uncertain significance	Dyskeratosis congenita	2021-05-18	criteria provided, single submitter	curation
Breakthrough Genomics, Breakthrough Genomics	RCV001760265	SCV005188745	uncertain significance	not provided		criteria provided, single submitter	not provided
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV005055159	SCV005689430	uncertain significance	Dyskeratosis congenita, autosomal recessive 2	2025-02-05	criteria provided, single submitter	clinical testing	The NHP2 c.289_290del p.(Met97ValfsTer2) change deletes two nucleotides and causes a frameshift and the creation of a premature stop codon. It is not expected to result in nonsense mediated decay. This variant has been reported in the heterozygous state in individuals with pulmonary fibrosis and shortened telomeres in which no other causal variant was identified (PMID: 31985013). Functional studies performed using patient-derived cells demonstrated an altered pre-rRNA profile suggesting a processing defect, but no reduction in snoRNA levels (PMID: 31985013). This variant has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV003151294	SCV003839771	uncertain significance	not specified	2022-04-15	no assertion criteria provided	clinical testing	DNA sequence analysis of the NHP2 gene demonstrated a two base pair deletion in exon 3, c.289_290del. This sequence change results in an amino acid frameshift and creates a premature stop codon two amino acids downstream of the change, p.Met97Valfs*2. This sequence change is predicted to result in an abnormal transcript, but may not undergo nonsense mediated decay. This deletion does not appear to have been previously described in individuals with NHP2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.025% in the Latino/Admixed American subpopulation (dbSNP rs762821341). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.