Submissions for variant NM_032756.4(HPDL):c.469T>C (p.Trp157Arg)

gnomAD frequency: 0.00005  dbSNP: rs567130416

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267924	SCV001446435	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001267924	SCV002028158	likely pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Identified with another HPDL variant on the opposite allele (in trans) in a patient in published literature with features of HPDL-related disorder and decreased HPDL protein levels in fibroblast cell lines (Husain et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32707086, 33634263, 35985664)
CeGaT Center for Human Genetics Tuebingen	RCV001267924	SCV002496878	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	HPDL: PM2, PM3, PS3:Supporting
Ambry Genetics	RCV002541634	SCV003747659	uncertain significance	Inborn genetic diseases	2021-09-10	criteria provided, single submitter	clinical testing	The c.469T>C (p.W157R) alteration is located in exon 1 of the HPDL gene. This alteration results from a T to C substitution at nucleotide position 469, causing the tryptophan (W) at amino acid position 157 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.0046% (11/238,592) total alleles studied. The highest observed frequency was 0.01% (10/104,900) in the European (non-Finnish) population. This alteration has been reported in trans with the c.753C>A (p.H251Q) alteration in a patient with delayed motor development, mild intellectual disability, microcephaly, spastic paraplegia, visual disturbance, and abnormal variation in muscle fiber diameter (Husain, 2020). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001267924	SCV003808761	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594263	SCV005086538	likely pathogenic	Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (MIM#619026) and spastic paraplegia 83, autosomal recessive (MIM#619027). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic, likely pathogenic and as a VUS by clinical laboratories in ClinVar; however, it was not stated whether these individuals had biallelic variants in HPDL. This variant has also been observed as compound heterozygous in an infant with spastic paraplegia, microcephaly, delayed motor development and mild intellectual disability (PMID: 32707086). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Western blot studies on fibroblast cells of a patient who is compound heterozygous for this variant and another missense variant showed significantly reduced HPDL protein levels (PMID: 32707086). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.835C>T; p.(Gln279*)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign