Submissions for variant NM_001097577.3(ANG):c.3G>A (p.Met1Ile)

gnomAD frequency: 0.00020  dbSNP: rs201068740

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000995107	SCV001149109	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112905	SCV001270619	uncertain significance	Amyotrophic lateral sclerosis type 9	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000995107	SCV001986295	uncertain significance	not provided	2020-08-28	criteria provided, single submitter	clinical testing	Previously identified in individuals with PD, ALS and/or FTLD; one of these individuals who was heterozygous for c.3G>T, which also leads to an M1? varinat, also harbored a pathogenic variant in the SOD1 gene (van Es, et al., 2011; Conforti, et al., 2008; Gellera et al., 2008; Tripolszki et al., 2019); Variant is located within the signal peptide and affecting the start codon, which may influence the correct translation of the protein; ; however, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. .; This variant is associated with the following publications: (PMID: 22190368, 17703939, 28444446, 18087731, 31025543)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000995107	SCV002436225	likely benign	not provided	2024-11-30	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV002463771	SCV002758563	uncertain significance	Amyotrophic lateral sclerosis type 10	2022-10-21	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2
PreventionGenetics, part of Exact Sciences	RCV003413785	SCV004116503	uncertain significance	ANG-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The ANG c.3G>A variant is predicted to disrupt the translation initiation site (Start Loss). This variant, which is located in the signal peptide region and has been previously described in the literature as Met-24Ile, has been reported in patients with sporadic amyotrophic lateral sclerosis (ALS), Parkinson disease/parkinsonism, or frontotemporal dementia (Conforti et al. 2008. PubMed ID: 17703939; Gellera et al. 2008. PubMed ID: 18087731; van Es et al. 2011. PubMed ID: 22190368; Marjanović et al. 2017. PubMed ID: 28444446; Ungaro et al. 2020. PubMed ID: 32951934). To our knowledge, functional studies have not been performed to better understand the biological relevance of this variant. This variant is reported in 0.097% of alleles in individuals of Ashkenazi Jewish descent, and 0.022% overall in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.