Submissions for variant NM_000478.6(ALPL):c.650delinsCTAA (p.Val217delinsAlaLys)

dbSNP: rs1553413155

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003126900	SCV003803524	likely pathogenic	not provided	2022-08-09	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid and insertion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34712267, 21638016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479197	SCV004223710	likely pathogenic	Hypophosphatasia	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.650delinsCTAA (p.Val217delinsAlaLys) results in an in-frame deletion-insertion that is predicted to delete Val amino acid and replace with Ala and Lys amino acids. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251464 control chromosomes (gnomAD). c.650delinsCTAA has been reported in the literature in bi-allelic individuals affected with autosomal recessive Hypophosphatasia (examples: Chang_2012, Zhang_2021,You_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21638016, 34712267, 31687651, 36427976). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV003126900	SCV004291724	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This variant, c.650delinsCTAA, is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the ALPL protein (p.Val217delinsAlaLys). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 21638016, 34712267, 36427976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000670798	SCV000795697	uncertain significance	Infantile hypophosphatasia	2017-11-17	flagged submission	clinical testing