Submissions for variant NM_004279.3(PMPCB):c.28T>G (p.Leu10Val)

gnomAD frequency: 0.00027  dbSNP: rs77305684

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001332397	SCV001524718	uncertain significance	Multiple mitochondrial dysfunctions syndrome 6	2019-02-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859291	SCV002311405	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the PMPCB protein (p.Leu10Val). This variant is present in population databases (rs77305684, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with PMPCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1030758). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001332397	SCV002768003	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.28T>G in exon 1 of 13 of the PMPCB gene. This substitution is predicted to create a minor amino acid change from leucine to valine at position 10 of the protein, NP_004270.2(PMPCB):p.(Leu10Val). The leucine at this position has low conservation (100 vertebrates, UCSC). It is located within the mitochondrial targeting sequence. In silico software predicts this variant to be benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.03% (77 heterozygotes, 0 homozygotes). It has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Ambry Genetics	RCV002546556	SCV003537321	likely benign	Inborn genetic diseases	2021-06-30	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.