Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute of Medical Genetics and Applied Genomics, |
RCV000019707 | SCV002555549 | likely pathogenic | Amyotrophic lateral sclerosis type 9 | 2022-07-29 | criteria provided, single submitter | clinical testing | gnomAD v3.1.2: rare and only 3 heterozygous samples (<50 years); PMID: 19153377: incomplete penetrance mentioned; highly conserved amino acid (aa) which is located within functional protein domain (only 2 aa beside 1 aa – H114 - of the catalytic residue triad; “damaging” by many prediction tools; PMID: 17886298: only 1 ALS- patient mentioned (without segregation analyses) and functional analyses in cell-line (HUVEC): LoF-variant > complete loss of protein function; PMID: 23047679: functional analyses in cell- line with the same result; PMID: 25382069: 1 fALS patient with additional 2 singel pathogenic variants in 2 other ALS genes (no segregation analyses) |
Prevention |
RCV003398548 | SCV004104639 | uncertain significance | ANG-related disorder | 2023-08-06 | criteria provided, single submitter | clinical testing | The ANG c.407C>T variant is predicted to result in the amino acid substitution p.Pro136Leu. This variant was reported in amyotrophic lateral sclerosis, although conclusive evidence of pathogenicity was not presented (also known as P112L, Wu et al 2007. PubMed ID: 17886298; Cady et al 2015. PubMed ID: 25382069). Functional studies suggested this variant results in partial loss of ribonucleolytic activity and complete loss of nuclear translocation activity (Padhi et al 2012. PubMed ID: 22384259; Thiyagarajan et al 2012. PubMed ID: 23047679; Padhi et al 2013. PubMed ID: 23665167). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-21162130-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
Labcorp Genetics |
RCV003565384 | SCV004315264 | uncertain significance | not provided | 2023-07-24 | criteria provided, single submitter | clinical testing | This variant is also known as p.Pro112Leu. 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. Experimental studies have shown that this missense change affects ANG function (PMID: 17886298, 23047679). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 18081). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 17886298). This variant is present in population databases (rs121909543, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 136 of the ANG protein (p.Pro136Leu). |
OMIM | RCV000019707 | SCV000040005 | pathogenic | Amyotrophic lateral sclerosis type 9 | 2007-12-01 | no assertion criteria provided | literature only |