Submissions for variant NM_002582.4(PARN):c.272A>G (p.Tyr91Cys)

gnomAD frequency: 0.00009  dbSNP: rs201765587

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000653141	SCV000775017	pathogenic	Dyskeratosis congenita, autosomal recessive 6; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4	2023-12-05	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 91 of the PARN protein (p.Tyr91Cys). This variant is present in population databases (rs201765587, gnomAD 0.02%). This missense change has been observed in individual(s) with Hoyeraal Hreidarsson syndrome (PMID: 31448843; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 542669). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PARN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PARN function (PMID: 31448843). For these reasons, this variant has been classified as Pathogenic.
Bertuch Lab, Baylor College of Medicine	RCV000850488	SCV000902456	pathogenic	Dyskeratosis congenita, autosomal recessive 6	2019-05-15	criteria provided, single submitter	in vitro	PARN is a ribodeadenylase. Biallelic PARN variants have been reported in 9 cases of Hoyeraal-Hreidarsson syndrome (HH)/dyskeratosis congenita. Monoallelic PARN variants are associated with IPF and more than 50 cases have been reported. This rare missense variant, p.Y91C, and novel insertion variant, p.I274*, were found in trans in two siblings with HH. Unaffected family members did not have both variants. Functional studies showed that PARN p.Y91C had reduced deadenylase activity and the p.I274* transcript likely underwent NMD. Studies with patient-derived samples showed the expected alteration of PARN target RNAs in one affected sibling. Telomere lengths were extremely short for both affected siblings. However, monoallelic variant carriers had variable telomere length, indicating incomplete penetrance of short telomeres in PARN variant carriers. In summary, this variant has strong evidence for being pathogenic according to ACMG 2015 guidelines and functional data, segregation data, and allelic data.
Genetic Services Laboratory, University of Chicago	RCV001816642	SCV002068936	uncertain significance	not specified	2019-11-14	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223900	SCV002502206	likely pathogenic	not provided	2022-03-09	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447549	SCV004175270	uncertain significance	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4	2023-07-05	criteria provided, single submitter	clinical testing	The PARN c.272A>G variant is classified as VUS (PS3_Moderate) The PARN c.272A>G variant is a single nucleotide change in exon 5/24 of the PARN gene, which is predicted to change the amino acid tyrosine at position 91 in the protein to cysteine. This variant is present at low frequency in population databases (gnomAD allele frequency = 0.0091%; 14 het and 0 hom in 152186 sequenced alleles; highest frequency = 0.019%, East Asian population) (PM2 not met). Computational predictions provide conflicting interpretations of pathogenicity for this variant (PP3 and BP4 not met). Functional studies showed that the p.(Tyr91Cys) variant had reduced deadenylase activity (10-fold lower than WT). The Y91C-mutated PARN polypeptide was perturbed in its deadenylation activity and suggest that the PARN-mediated deadenylation activity in individuals in this pedigree carrying the mutation was affected. However, the affected pedigree shows pseudo-dominant inheritance, and the heterozygous carriers of the Y91C variant only displayed reduced telomeres, without bone marrow failure (Dodson et al, 2019; PMID:31448843). (PS3_moderate). The variant has been reported in dbSNP (rs201765587) and in the HGMD database: CM1918160. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 542669).