Submissions for variant NM_004279.3(PMPCB):c.1336A>G (p.Asn446Asp)

gnomAD frequency: 0.00172  dbSNP: rs144744182

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001727416	SCV001962075	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001727416	SCV002469051	likely benign	not provided	2023-06-20	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471137	SCV002768050	uncertain significance	Multiple mitochondrial dysfunctions syndrome 6	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_004279.2(PMPCB):c.1336A>G in exon 12 of 13 of the PMPCB gene. This substitution is predicted to create a minor amino acid change from asparagine to aspartic acid at position 446 of the protein, NP_004270.2(PMPCB):p.(Asn446Asp). The asparagine at this position has low conservation (100 vertebrates, UCSC), and is located within the Pqql superfamily functional domain. In silico software predictions of the pathogenicity of this variant is conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.15%% (428 heterozygotes, 0 homozygotes). The variant has not been previously reported in a clinical case. Analysis of parental samples shows this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
Ambry Genetics	RCV004656641	SCV005155493	likely benign	Inborn genetic diseases	2024-05-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003910980	SCV004727418	likely benign	PMPCB-related disorder	2022-02-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).