Submissions for variant NM_002582.4(PARN):c.19A>C (p.Asn7His)

gnomAD frequency: 0.00004  dbSNP: rs1371498176

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001211515	SCV001383058	uncertain significance	Dyskeratosis congenita, autosomal recessive 6; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 7 of the PARN protein (p.Asn7His). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with dyskeratosis congenita and pulmonary fibrosis (PMID: 26482878, 28414520). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 834008). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
GeneDx	RCV001759929	SCV001989049	uncertain significance	not provided	2019-07-09	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a family with interstitial lung disease in published literature (Kropski et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico splice predictor analyses are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26482878, 28414520)
University of Washington Center for Mendelian Genomics, University of Washington	RCV001034550	SCV001197915	uncertain significance	Pulmonary fibrosis; Familial Interstitial Pneumonia		no assertion criteria provided	research
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509594	SCV002547354	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Genetic Services Laboratory, University of Chicago	RCV003151266	SCV003839810	uncertain significance	not specified	2022-05-17	no assertion criteria provided	clinical testing	DNA sequence analysis of the PARN gene demonstrated a sequence change, c.19A>C, in exon 1 that results in an amino acid change, p.Asn7His. This sequence change has been previously described in an individual with dyskeratosis congenita who also had a large deletion encompassing the PARN gene on the other allele (PMID: 26482878). It has also been described in the heterozygous state in an individual with pulmonary fibrosis (PMID: 28414520). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0031 % (dbSNP rs1371498176). The p.Asn7His change affects a poorly conserved amino acid residue located in a domain of the PARN protein that is known to be functional. The p.Asn7His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asn7His change remains unknown at this time.