Submissions for variant NM_005797.4(MPZL2):c.72del (p.Ile24fs)

gnomAD frequency: 0.00069  dbSNP: rs752672077

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820138	SCV000960835	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile24Metfs*22) in the MPZL2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MPZL2 cause disease. This variant is present in population databases (rs752672077, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with nonsyndromic hearing loss (PMID: 29961571, 29982980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585268). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000710018	SCV001526024	pathogenic	Hearing loss, autosomal recessive 111	2018-11-30	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple consanguineous families with slowly progressive, moderate to severe hearing loss [PMID 29982980, 29961571]
Neurogenetic Laboratory, Second Faculty of Medicine, Charles University	RCV000710018	SCV001571597	likely pathogenic	Hearing loss, autosomal recessive 111	2021-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000820138	SCV001825233	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29961571, 29982980, 34426522, 34062854, 33234333, 33594163, 27535533, 35599849, 36147510)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000710018	SCV002555687	pathogenic	Hearing loss, autosomal recessive 111	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: MPZL2 c.72delA (p.Ile24MetfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Hearing Loss in HGMD. The variant allele was found at a frequency of 0.00081 in 250850 control chromosomes (gnomAD). c.72delA has been reported in the literature in multiple homozygous individuals affected with Hearing Loss, Autosomal Recessive 111 and seggregated with the disease (example: Bademci_2018). These data indicate that the variant is very likely to be associated with disease. Six submitters provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000710018	SCV002579296	pathogenic	Hearing loss, autosomal recessive 111	2021-10-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965455	SCV004778128	pathogenic	MPZL2-related condition	2023-11-21	criteria provided, single submitter	clinical testing	The MPZL2 c.72delA variant is predicted to result in a frameshift and premature protein termination (p.Ile24Metfs*22). This variant has been reported in patients with autosomal recessive hearing loss (Bademci. 2018. PubMed ID: 29982980; Wesdorp. 2018. PubMed ID: 29961571; Safka Brozkova. 2021. PubMed ID: 34062854). This variant is reported in 0.38% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-118133798-CT-C). Frameshift variants in MPZL2 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000710018	SCV000840383	pathogenic	Hearing loss, autosomal recessive 111	2019-02-22	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000820138	SCV001953019	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000820138	SCV001967065	pathogenic	not provided		no assertion criteria provided	clinical testing