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	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. Studies have shown that this variant alters PNPT1 gene expression (PMID: 31752325). ClinVar contains an entry for this variant (Variation ID: 869396). 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. 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.