Submissions for variant NM_213720.3(CHCHD10):c.239C>T (p.Pro80Leu)

gnomAD frequency: 0.00016  dbSNP: rs775332895

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000558062	SCV000653012	likely benign	Lower motor neuron syndrome with late-adult onset; Frontotemporal dementia and/or amyotrophic lateral sclerosis 2; Autosomal dominant mitochondrial myopathy with exercise intolerance	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000990378	SCV001141336	benign	Lower motor neuron syndrome with late-adult onset	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092755	SCV001249403	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	CHCHD10: BP4, BS1
Molecular Genetics, Royal Melbourne Hospital	RCV002221211	SCV002498671	uncertain significance	Amyotrophic lateral sclerosis	2022-04-05	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace proline with leucine at codon 80 of the CHCHD10 protein, p.(Pro80Leu). The proline residue is highly conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a moderate physicochemical difference between proline and leucine. The variant is present in a large population cohort at a frequency of 0.03% (rs775332895, 76/268,368 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.3% in the Ashkenazi Jewish population (33/10,032 alleles in gnomAD v2.1). It has been reported as benign, likely benign, a variant of uncertain significance, and pathogenic (ClinVar ID: 204292). The variant has been identified in sporadic and familial amyotrophic lateral sclerosis cases (PMID: 25576308, 30014597, 31690696). It abrogates protein function in the nucleus and mitochondria, reducing respiration and increasing reactive oxygen species in an in vitro functional assay (PMID: 29540477). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PS3_Supporting.
Ambry Genetics	RCV002453685	SCV002738510	likely benign	Inborn genetic diseases	2021-05-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV003927730	SCV004739856	likely benign	CHCHD10-related condition	2020-11-02	criteria provided, single submitter	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).
GeneReviews	RCV000192233	SCV000239872	not provided	Frontotemporal dementia and/or amyotrophic lateral sclerosis 2		no assertion provided	literature only
GenomeConnect, ClinGen	RCV000558062	SCV000840207	not provided	Lower motor neuron syndrome with late-adult onset; Frontotemporal dementia and/or amyotrophic lateral sclerosis 2; Autosomal dominant mitochondrial myopathy with exercise intolerance		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.