Submissions for variant NM_033109.5(PNPT1):c.1818T>G (p.Val606=)

dbSNP: rs1049082567

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kids Research, The Children's Hospital at Westmead	RCV001089489	SCV001244733	pathogenic	Combined oxidative phosphorylation defect type 13; Autosomal recessive nonsyndromic hearing loss 70		criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471035	SCV002767651	pathogenic	Combined oxidative phosphorylation defect type 13	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. cDNA studies performed on cultured fibroblast from this patient confirmed aberrant splicing resulting in a frameshift and premature termination codon, p.(Val607Lysfs*21) (PMID: 31752325) (P) 0210 – Synonymous variant proven to affect splicing/expression of the transcript with a known effect on protein structure. RNA studies have shown that this variant causes aberrant splicing (PMID: 31752325) (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Other NMD predicted variants have previously been reported in patients with PNPT1-related disorders (ClinVar, PMID: 28594066; 30244537) (P) 0807 - Variant has not previously been reported in another individual, however, it has been reported in this patient (PMID: 31752325). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence support abnormal protein function. Functional studies performed on this patient’s fibroblast showed a reduction in complex I and complex IV activities, as well as accumulation of unprocessed mitochondrial transcripts (PMID: 31752325)(P) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease.* (P) 1205 - Variant is maternally inherited.* (N) *Whole genome TRIO analysis was performed at the Garvan Institute under research settings. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002554797	SCV003019249	pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of PNPT1-related conditions (PMID: 31752325, 32313153). 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: 869396). Studies have shown that this variant alters PNPT1 gene expression (PMID: 31752325). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 31752325). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 606 of the PNPT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PNPT1 protein.