ClinVar Miner

Submissions for variant NM_138361.5(LRSAM1):c.94G>A (p.Asp32Asn) (rs150784835)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463775 SCV000547853 uncertain significance Charcot-Marie-Tooth disease type 2P 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 32 of the LRSAM1 protein (p.Asp32Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs150784835, ExAC 0.02%). This variant has not been reported in the literature in individuals with a LRSAM1-related disease. ClinVar contains an entry for this variant (Variation ID: 408269). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on LRSAM1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000493063 SCV000582291 uncertain significance not provided 2017-05-11 criteria provided, single submitter clinical testing The D32N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 2/11,578 (0.02%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016). The D32N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in someproperties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant is not located within the RING domain. Therefore, based on the currently available information, it isunclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000463775 SCV001331067 likely benign Charcot-Marie-Tooth disease type 2P 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173637 SCV001336739 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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