Submissions for variant NM_015426.5(POC1A):c.241C>T (p.Arg81Ter)

gnomAD frequency: 0.00001  dbSNP: rs397514487

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000030716	SCV000784452	pathogenic	Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome	2018-03-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001564537	SCV001787719	pathogenic	not provided	2019-07-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32552793, 31130284, 25558065, 26633546, 26791357, 22840364)
Blueprint Genetics	RCV001564537	SCV001832422	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001564537	SCV002238127	pathogenic	not provided	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg81*) in the POC1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POC1A are known to be pathogenic (PMID: 22840364, 26336158, 26374189). This variant is present in population databases (rs397514487, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with SOFT syndrome (PMID: 22840364, 26791357). ClinVar contains an entry for this variant (Variation ID: 37062). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV000030716	SCV002576353	pathogenic	Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000030716	SCV005329497	pathogenic	Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome	2023-05-20	criteria provided, single submitter	clinical testing	The observed stop gained variant c.241C>T(p.Arg81Ter) in POC1A gene has been reported previously in homozygous and compound heterozygous state in individuals with SOFT syndrome (Mericq V, et al., 2022, Ko JM, et al., 2016). The c.241C>T variant has 0.003% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Computational evidence (Mutation Taster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Barraza-García J, et al., 2016). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030716	SCV005422176	pathogenic	Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome	2024-10-23	criteria provided, single submitter	clinical testing	Variant summary: POC1A c.241C>T (p.Arg81X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250974 control chromosomes (gnomAD). c.241C>T has been reported in the literature in individuals affected with Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome (Min Ko_2016, Maddirevula_2020). 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: 32552793, 26791357). ClinVar contains an entry for this variant (Variation ID: 37062). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000030716	SCV000053377	pathogenic	Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome	2012-08-10	no assertion criteria provided	literature only
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001838528	SCV000196452	likely pathogenic	Ateleiotic dwarfism	2014-12-01	no assertion criteria provided	research