Submissions for variant NM_000188.3(HK1):c.1969G>A (p.Asp657Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324313	SCV004030079	uncertain significance	not specified	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: HK1 c.1969G>A (p.Asp657Asn) results in a conservative amino acid change located in the N-terminal domain (IPR022672) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251216 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1969G>A has been reported in the literature in the heterozygous state as a de novo occurrence in an individual with global developmental delay and hypotonia who had a working diagnosis of autism spectrum disorder with a differential diagnosis of congenital myasthenic syndrome (Turner_2019, Poole_2023). The proband had no MRI brain abnormalities and ptosis by the end of the day and occasional complaints of blurred vision were the only reported visual symptoms (Poole_2023). This report does not provide unequivocal conclusions about association of the variant with HK1-Related Disorders. 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: 31785789, 36639056). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003661043	SCV004376279	pathogenic	not provided	2023-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt HK1 protein function. This missense change has been observed in individual(s) with a neurodevelopmental disorder (PMID: 31785789, 36639056). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 657 of the HK1 protein (p.Asp657Asn).