Submissions for variant NM_005321.3(H1-4):c.441dup (p.Lys148fs)

dbSNP: rs1131690806

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000782004	SCV000920464	pathogenic	not provided	2018-01-09	criteria provided, single submitter	clinical testing
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital	RCV000492407	SCV000925236	pathogenic	Rahman syndrome	2019-05-01	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000492407	SCV001440316	pathogenic	Rahman syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000782004	SCV001468922	pathogenic	not provided		criteria provided, single submitter	clinical testing
GeneDx	RCV000782004	SCV001811898	pathogenic	not provided	2020-04-06	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 72 amino acids are lost and replaced with 47 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31910894, 31447100, 31400068, 28475857, 25081361, 29704315)
3billion	RCV000492407	SCV003841324	pathogenic	Rahman syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000428606). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000492407	SCV005397415	pathogenic	Rahman syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This sequence variant is a one-nucleotide duplication (dupC) at coding position 441 in the H1-4 gene. This variant has been referred to as c.437dupC and c.441dup in the published literature. This duplication results in a premature termition sigl 48 codons downstream of the frameshift introduced at codon 148. This variant is absent from the gnomAD population database (0 of approximately 230,000 alleles). This is a previously reported variant (ClinVar) that has been identified in multiple D sequencing studies in individuals expressing variable clinical phenotypes including, but not limited to, intellectual disability, autism, microcephaly, seizures, brain atrophy, scoliosis, hip dislocation, dysmorphic features, hyperpigmented lesions in the trunk and distinctive facial gestalt (PMID: 28475857, 29704315, 31130284, 31400068). An in vitro functiol study showed that this variant disrupts proper compaction of D causing a dramatic reduction in proliferation rate and accelerated senescence of patient derived cultured cells (PMID: 31447100). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PS3, PS4, PVS1
OMIM	RCV000492407	SCV000580688	pathogenic	Rahman syndrome	2017-06-27	no assertion criteria provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000492407	SCV002011701	pathogenic	Rahman syndrome	2021-09-13	no assertion criteria provided	clinical testing
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University	RCV003984842	SCV004801121	pathogenic	Auditory neuropathy spectrum disorder	2023-10-08	no assertion criteria provided	clinical testing