Submissions for variant NM_001368809.2(AMPD2):c.971G>T (p.Arg324Leu)

dbSNP: rs746332433

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692141	SCV000819950	likely pathogenic	Hereditary spastic paraplegia 63; Pontocerebellar hypoplasia type 9	2021-05-25	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces arginine with leucine at codon 378 of the AMPD2 protein (p.Arg378Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of AMPD2-related conditions (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 571097). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg378 amino acid residue in AMPD2. Other variant(s) that disrupt this residue have been observed in individuals with AMPD2-related conditions (PMID: 29463858, Invitae), which suggests that this may be a clinically significant amino acid residue.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586881	SCV005075924	uncertain significance	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: AMPD2 c.971G>T (p.Arg324Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.971G>T in individuals affected with Pontocerebellar Hypoplasia, Type 9 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 571097). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV004760714	SCV005370920	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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: 29463858, 27694994)