Submissions for variant NM_001605.3(AARS1):c.212A>G (p.Asn71Ser)

dbSNP: rs757167895

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702635	SCV000831496	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 71 of the AARS protein (p.Asn71Ser). This variant is present in population databases (rs757167895, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of AARS-related conditions (PMID: 28902413). ClinVar contains an entry for this variant (Variation ID: 579370). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AARS protein function. This variant disrupts the p.Asn71 amino acid residue in AARS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22009580, 22206013). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Illumina Laboratory Services, Illumina	RCV001118520	SCV001276810	uncertain significance	Charcot-Marie-Tooth disease axonal type 2N	2017-04-28	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV002245611	SCV002513682	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a patient with CMT2N and HMN; no other information was provided (Dohrn et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28902413, 25817015, 22009580, 22206013)
Ambry Genetics	RCV002536362	SCV003756280	uncertain significance	Inborn genetic diseases	2022-02-11	criteria provided, single submitter	clinical testing	The c.212A>G (p.N71S) alteration is located in exon 3 (coding exon 2) of the AARS gene. This alteration results from a A to G substitution at nucleotide position 212, causing the asparagine (N) at amino acid position 71 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the AARS c.1212A>G alteration was observed in 0.0004% (1/251,478) of total alleles studied. This variant was detected in the heterozygous state in one patient with neuropathy (Dohrn, 2017). This amino acid position is completely conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.